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Sample records for androgen independent prostate

  1. Hedgehog/Gli supports androgen signaling in androgen deprived and androgen independent prostate cancer cells

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    Shtutman Michael

    2010-04-01

    Full Text Available Abstract Background Castration resistant prostate cancer (CRPC develops as a consequence of hormone therapies used to deplete androgens in advanced prostate cancer patients. CRPC cells are able to grow in a low androgen environment and this is associated with anomalous activity of their endogenous androgen receptor (AR despite the low systemic androgen levels in the patients. Therefore, the reactivated tumor cell androgen signaling pathway is thought to provide a target for control of CRPC. Previously, we reported that Hedgehog (Hh signaling was conditionally activated by androgen deprivation in androgen sensitive prostate cancer cells and here we studied the potential for cross-talk between Hh and androgen signaling activities in androgen deprived and androgen independent (AI prostate cancer cells. Results Treatment of a variety of androgen-deprived or AI prostate cancer cells with the Hh inhibitor, cyclopamine, resulted in dose-dependent modulation of the expression of genes that are regulated by androgen. The effect of cyclopamine on endogenous androgen-regulated gene expression in androgen deprived and AI prostate cancer cells was consistent with the suppressive effects of cyclopamine on the expression of a reporter gene (luciferase from two different androgen-dependent promoters. Similarly, reduction of smoothened (Smo expression with siRNA co-suppressed expression of androgen-inducible KLK2 and KLK3 in androgen deprived cells without affecting the expression of androgen receptor (AR mRNA or protein. Cyclopamine also prevented the outgrowth of AI cells from androgen growth-dependent parental LNCaP cells and suppressed the growth of an overt AI-LNCaP variant whereas supplemental androgen (R1881 restored growth to the AI cells in the presence of cyclopamine. Conversely, overexpression of Gli1 or Gli2 in LNCaP cells enhanced AR-specific gene expression in the absence of androgen. Overexpressed Gli1/Gli2 also enabled parental LNCaP cells to

  2. Prostate cancer: molecular biology of early progression to androgen independence.

    Science.gov (United States)

    Sadar, M D; Hussain, M; Bruchovsky, N

    1999-12-01

    To improve the therapy for prostate cancer, it will be necessary to address the problems of progression to androgen independence and the process of metastatic spread of tumour. The complexity of the latter condition is likely to mitigate against the immediate development of relevant therapeutic approaches. However, the basis of androgen independence appears to be a problem of simpler dimensions and more amenable to treatment with current therapeutic technology. Since early tumour progression can be detected by an incomplete prostate-specific antigen (PSA) response to androgen withdrawal therapy, a study of the molecular biology of PSA gene regulation may well provide insight into new methods for preventing or delaying this problem. Mounting evidence suggests that ligand-independent activation of the androgen receptor may be one underlying mechanism of androgen independence. In the absence of androgen, a compensatory increase in the activity of cAMP-dependent protein kinase (PKA) enhances the ability of the androgen receptor to bind to the response elements regulating PSA gene expression. The activation of the androgen receptor through up-regulation of the PKA signal transduction pathway involves the amino-terminus of the androgen receptor, the function of which may be altered either by modifications such as phosphorylation, or through interactions with co-regulators or other proteins. Of therapeutic interest is the fact that this effect can be counteracted experimentally by the anti-androgen, bicalutamide, and clinically by several other similar agents. We speculate that the inhibition of PKA-activated androgen receptor might also be accomplished by decoy molecules that can bind to the relevant activated site on the amino-terminus or competitively interact with proteins recruited by the PKA pathway that are responsible for activating the receptor in the absence of androgen. Such molecules might include small mimetic substances or agents that can gain access to the

  3. Regulation of expression of Na+,K+-ATPase in androgen-dependent and androgen-independent prostate cancer

    NARCIS (Netherlands)

    L.J. Blok (Leen); G.T.G. Chang; M. Steenbeek-Slotboom (M.); W.M. van Weerden (Wytske); H.G. Swarts; J.J.H.H.M. de Pont (J. J H H M); G.J. van Steenbrugge (Gert Jan); A.O. Brinkmann (Albert)

    1999-01-01

    textabstractThe β1-subunit of Na+,K+-ATPase was isolated and identified as an androgen down-regulated gene. Expression was observed at high levels in androgen-independent as compared to androgen-dependent (responsive) human prostate cancer cell lines and xenografts when grown in the presence of

  4. Evolving perspectives of the role of novel agents in androgen-independent prostate cancer

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    Sujith Kalmadi

    2008-01-01

    Full Text Available Metastatic androgen-independent prostate cancer presents an intriguing clinical challenge, with a subtle interaction between hormone-responsive and refractory tumor cell elements. The treatment of advanced prostate carcinoma, which had remained stagnant for several decades following the understanding of the link between androgenic stimulation and carcinogenesis, has now started to make steady headway with chemotherapy and targeted approaches. Metastatic prostate cancer is almost always treated with initial androgen deprivation, in various forms. However, despite such treatment androgen-independent prostate cancer cells eventually emerge and progress to threaten life. The therapeutic objectives for treatment of metastatic prostate cancer are to maintain the quality of life and prolong survival. The out-dated nihilistic dogma of deferring chemotherapy until the most advanced stages in advanced prostate cancer is now falling by the wayside with the development of newer effective, tolerable agents.

  5. Neutral Endopeptidase Inhibits Neuropeptide Mediated Growth of Androgen-Independent Prostate Cancer

    National Research Council Canada - National Science Library

    Dai, Jie

    2000-01-01

    ...), a cell-surface peptidase which inactivates active peptides and reduces local concentrations of peptide available for receptor binding and signal transduction, in the growth inhibition of androgen-independent (Al) prostate cancer...

  6. The PPARγ ligand ciglitazone regulates androgen receptor activation differently in androgen-dependent versus androgen-independent human prostate cancer cells

    International Nuclear Information System (INIS)

    Moss, Patrice E.; Lyles, Besstina E.; Stewart, LaMonica V.

    2010-01-01

    The androgen receptor (AR) regulates growth and progression of androgen-dependent as well as androgen-independent prostate cancer cells. Peroxisome proliferator-activated receptor gamma (PPARγ) agonists have been reported to reduce AR activation in androgen-dependent LNCaP prostate cancer cells. To determine whether PPARγ ligands are equally effective at inhibiting AR activity in androgen-independent prostate cancer, we examined the effect of the PPARγ ligands ciglitazone and rosiglitazone on C4-2 cells, an androgen- independent derivative of the LNCaP cell line. Luciferase-based reporter assays and Western blot analysis demonstrated that PPARγ ligand reduced dihydrotestosterone (DHT)-induced increases in AR activity in LNCaP cells. However, in C4-2 cells, these compounds increased DHT-induced AR driven luciferase activity. In addition, ciglitazone did not significantly alter DHT-mediated increases in prostate specific antigen (PSA) protein or mRNA levels within C4-2 cells. siRNA-based experiments demonstrated that the ciglitazone-induced regulation of AR activity observed in C4-2 cells was dependent on the presence of PPARγ. Furthermore, overexpression of the AR corepressor cyclin D1 inhibited the ability of ciglitazone to induce AR luciferase activity in C4-2 cells. Thus, our data suggest that both PPARγ and cyclin D1 levels influence the ability of ciglitazone to differentially regulate AR signaling in androgen-independent C4-2 prostate cancer cells.

  7. Analysis of the molecular networks in androgen dependent and independent prostate cancer revealed fragile and robust subsystems.

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    Ryan Tasseff

    Full Text Available Androgen ablation therapy is currently the primary treatment for metastatic prostate cancer. Unfortunately, in nearly all cases, androgen ablation fails to permanently arrest cancer progression. As androgens like testosterone are withdrawn, prostate cancer cells lose their androgen sensitivity and begin to proliferate without hormone growth factors. In this study, we constructed and analyzed a mathematical model of the integration between hormone growth factor signaling, androgen receptor activation, and the expression of cyclin D and Prostate-Specific Antigen in human LNCaP prostate adenocarcinoma cells. The objective of the study was to investigate which signaling systems were important in the loss of androgen dependence. The model was formulated as a set of ordinary differential equations which described 212 species and 384 interactions, including both the mRNA and protein levels for key species. An ensemble approach was chosen to constrain model parameters and to estimate the impact of parametric uncertainty on model predictions. Model parameters were identified using 14 steady-state and dynamic LNCaP data sets taken from literature sources. Alterations in the rate of Prostatic Acid Phosphatase expression was sufficient to capture varying levels of androgen dependence. Analysis of the model provided insight into the importance of network components as a function of androgen dependence. The importance of androgen receptor availability and the MAPK/Akt signaling axes was independent of androgen status. Interestingly, androgen receptor availability was important even in androgen-independent LNCaP cells. Translation became progressively more important in androgen-independent LNCaP cells. Further analysis suggested a positive synergy between the MAPK and Akt signaling axes and the translation of key proliferative markers like cyclin D in androgen-independent cells. Taken together, the results support the targeting of both the Akt and MAPK

  8. Identification of an anabolic selective androgen receptor modulator that actively induces death of androgen-independent prostate cancer cells.

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    Schmidt, Azriel; Meissner, Robert S; Gentile, Michael A; Chisamore, Michael J; Opas, Evan E; Scafonas, Angela; Cusick, Tara E; Gambone, Carlo; Pennypacker, Brenda; Hodor, Paul; Perkins, James J; Bai, Chang; Ferraro, Damien; Bettoun, David J; Wilkinson, Hilary A; Alves, Stephen E; Flores, Osvaldo; Ray, William J

    2014-09-01

    Prostate cancer (PCa) initially responds to inhibition of androgen receptor (AR) signaling, but inevitably progresses to hormone ablation-resistant disease. Much effort is focused on optimizing this androgen deprivation strategy by improving hormone depletion and AR antagonism. However we found that bicalutamide, a clinically used antiandrogen, actually resembles a selective AR modulator (SARM), as it partially regulates 24% of endogenously 5α-dihydrotestosterone (DHT)-responsive genes in AR(+) MDA-MB-453 breast cancer cells. These data suggested that passive blocking of all AR functions is not required for PCa therapy. Hence, we adopted an active strategy that calls for the development of novel SARMs, which induce a unique gene expression profile that is intolerable to PCa cells. Therefore, we screened 3000 SARMs for the ability to arrest the androgen-independent growth of AR(+) 22Rv1 and LNCaP PCa cells but not AR(-) PC3 or DU145 cells. We identified only one such compound; the 4-aza-steroid, MK-4541, a potent and selective SARM. MK-4541 induces caspase-3 activity and cell death in both androgen-independent, AR(+) PCa cell lines but spares AR(-) cells or AR(+) non-PCa cells. This activity correlates with its promoter context- and cell-type dependent transcriptional effects. In rats, MK-4541 inhibits the trophic effects of DHT on the prostate, but not the levator ani muscle, and triggers an anabolic response in the periosteal compartment of bone. Therefore, MK-4541 has the potential to effectively manage prostatic hypertrophic diseases owing to its antitumor SARM-like mechanism, while simultaneously maintaining the anabolic benefits of natural androgens. Copyright © 2014 Elsevier Ltd. All rights reserved.

  9. Characterizing and Targeting Androgen Receptor Pathway-Independent Prostate Cancer

    Science.gov (United States)

    2013-11-01

    chromosomal anomalies in metastatic prostatic carcinoma by fluorescence in situ hybridization. Cancer Res 57: 524–531. 21. Bernard D, Pourtier-Manzanedo A...of prostate cancer metastasis. Red depicts chromosomal regions with copy number gain and Blue depicts regions with copy number loss. X-axis (columns...of figure the full human genome ordered by chromosome (1-X,Y). The Y-Axis (Rows) are individual patients with multiple tumors per patient. Note

  10. Lycopene differentially induces quiescence and apoptosis in androgen-responsive and -independent prostate cancer cell lines.

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    Ivanov, Nikita I; Cowell, Simon P; Brown, Paula; Rennie, Paul S; Guns, Emma S; Cox, Michael E

    2007-04-01

    Lycopene has been credited with a number of health benefits including a decrease in prostate cancer risk. Our study investigates the molecular mechanism underlying anti-cancer activity of lycopene-based products in androgen-responsive (LNCaP) and androgen-independent (PC3) cells. The effect of lycopene-based agents on prostate cancer growth and survival were examined using proliferation assays, bromodeoxyuridine incorporation and flow cytometric analysis of cellular DNA content. Biochemical effects of lycopene treatment were investigated by immunoblotting for changes in the absolute levels and phosphorylation states of cell cycle regulatory and signalling proteins. LNCaP and PC3 cells treated with the lycopene-based agents undergo mitotic arrest, accumulating in G0/G1 phase. Immunoblot screening indicated that lycopene's antiproliferative effects are likely achieved through a block in G1/S transition mediated by decreased levels of cyclins D1 and E and cyclin dependent kinase 4 and suppressed Retinoblastoma phosphorylation. These responses correlated with decreased insulin-like growth factor-I receptor expression and activation, increased insulin-like growth factor binding protein 2 expression and decreased AKT activation. Exposure to lycopene at doses as low as 10 nM for 48 h induced a profound apoptotic response in LNCaP cells. In contrast PC3 cells were resistant to apoptosis at doses up to 1 microM. Lycopene exposure can suppress phosphatidylinositol 3-kinase-dependent proliferative and survival signalling in androgen-responsive LNCaP and androgen-independent PC3 cells suggesting that the molecular mechanisms for the cytostatic and cytotoxic actions of lycopene involve induction of G0/G1 cell cycle arrest. This study supports further examination of lycopene as a potential agent for both the prevention and treatment of prostate cancer.

  11. Androgen-independent proliferation of LNCaP prostate cancer cells infected by xenotropic murine leukemia virus-related virus

    International Nuclear Information System (INIS)

    Kakoki, Katsura; Kamiyama, Haruka; Izumida, Mai; Yashima, Yuka; Hayashi, Hideki; Yamamoto, Naoki; Matsuyama, Toshifumi; Igawa, Tsukasa; Sakai, Hideki; Kubo, Yoshinao

    2014-01-01

    Highlights: • XMRV infection induces androgen-independent growth in LNCaP cells. • XMRV infection reduces expression of androgen receptor. • XMRV promotes appearance of androgen blocker-resistant prostate cancer cells. - Abstract: Xenotropic murine leukemia virus-related virus (XMRV) is a novel gammaretrovirus that was originally isolated from human prostate cancer. It is now believed that XMRV is not the etiologic agent of prostate cancer. An analysis of murine leukemia virus (MLV) infection in various human cell lines revealed that prostate cancer cell lines are preferentially infected by XMRV, and this suggested that XMRV infection may confer some sort of growth advantage to prostate cancer cell lines. To examine this hypothesis, androgen-dependent LNCaP cells were infected with XMRV and tested for changes in certain cell growth properties. We found that XMRV-infected LNCaP cells can proliferate in the absence of the androgen dihydrotestosterone. Moreover, androgen receptor expression is significantly reduced in XMRV-infected LNCaP cells. Such alterations were not observed in uninfected and amphotropic MLV-infected LNCaP cells. This finding explains why prostate cancer cell lines are preferentially infected with XMRV

  12. The Role of the Co-Chaperone, CHIP, in Androgen Independent Prostate Cancer

    National Research Council Canada - National Science Library

    Hassen, Waleed A

    2008-01-01

    Expression of Chip, a Co-Chaperone Which Interacts with the Androgen Receptor, Results in Loss of AR Expression and Growth Inhibition of Prostate Cancer Cells Waleed Hassen, Xiaoyoung Zheng, Antonio...

  13. Differential Effects of Leptin on the Invasive Potential of Androgen-Dependent and -Independent Prostate Carcinoma Cells

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    Dayanand D. Deo

    2008-01-01

    Full Text Available Obesity has been linked with an increased risk of prostate cancer. The formation of toxic free oxygen radicals has been implicated in obesity mediated disease processes. Leptin is one of the major cytokines produced by adipocytes and controls body weight homeostasis through food intake and energy expenditure. The rationale of the study was to determine the impact of leptin on the metastatic potential of androgen-sensitive (LNCaP cells as well as androgen-insensitive (PC-3 and DU-145 cells. At a concentration of 200_nm, LNCaP cells showed a significant increase (20% above control; P<.0001 in cellular proliferation without any effect on androgen-insensitive cells. Furthermore, exposure to leptin caused a significant (P<.01 to P<.0001 dose-dependent decrease in migration and invasion of PC3 and Du-145 prostate carcinoma cell lines. At the molecular level, exposure of androgen-independent prostate cancer cells to leptin stimulates the phosphorylation of MAPK at early time point as well as the transcription factor STAT3, suggesting the activation of the intracellular signaling cascade upon leptin binding to its cognate receptor. Taken together, these results suggest that leptin mediates the invasive potential of prostate carcinoma cells, and that this effect is dependent on their androgen sensitivity.

  14. The Hsp90 Inhibitor, 17-AAG, Prevents the Ligand-Independent Nuclear Localization of Androgen Receptor in Refractory Prostate Cancer Cells

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    Saporita, Anthony J.; Ai, Junkui; Wang, Zhou

    2010-01-01

    BACKGROUND Androgen receptor (AR) is the key molecule in androgen-refractory prostate cancer. Despite androgen ablative conditions, AR remains active and is necessary for the growth of androgen-refractory prostate cancer cells. Nuclear localization of AR is a prerequisite for its transcriptional activation. We examined AR localization in androgen-dependent and androgen-refractory prostate cancer cells. METHODS AND RESULTS We demonstrate increased nuclear localization of a GFP-tagged AR in the absence of hormone in androgen-refractory C4-2 cells compared to parental androgen-sensitive human prostate cancer LNCaP cells. Analysis of AR mutants impaired in ligand-binding indicates that the nuclear localization of AR in C4-2 cells is truly androgen-independent. The hsp90 inhibitor, 17-allylamino-17-demethoxygeldanamycin (17-AAG), inhibits basal PSA expression and disrupts the ligand-independent nuclear localization of AR at doses much lower than required to inhibit androgen-induced nuclear import. CONCLUSIONS Hsp90 is a key regulator of ligand-independent nuclear localization and activation of AR in androgen-refractory prostate cancer cells. PMID:17221841

  15. Hypoxia-Independent Downregulation of Hypoxia-Inducible Factor 1 Targets by Androgen Deprivation Therapy in Prostate Cancer

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    Ragnum, Harald Bull [Department of Radiation Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Røe, Kathrine [Department of Radiation Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Division of Medicine, Department of Oncology, Akershus University Hospital, Lørenskog (Norway); Holm, Ruth; Vlatkovic, Ljiljana [Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Nesland, Jahn Marthin [Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Medical Faculty, University of Oslo, Oslo (Norway); Aarnes, Eva-Katrine [Department of Radiation Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Ree, Anne Hansen [Division of Medicine, Department of Oncology, Akershus University Hospital, Lørenskog (Norway); Medical Faculty, University of Oslo, Oslo (Norway); Flatmark, Kjersti [Department of Tumor Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Department of Gastrointestinal Surgery, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Seierstad, Therese [Department of Radiology and Nuclear Medicine, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Faculty of Health Sciences, Buskerud University College, Drammen (Norway); Lilleby, Wolfgang [Department of Oncology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Lyng, Heidi, E-mail: heidi.lyng@rr-research.no [Department of Radiation Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway)

    2013-11-15

    Purpose: We explored changes in hypoxia-inducible factor 1 (HIF1) signaling during androgen deprivation therapy (ADT) of androgen-sensitive prostate cancer xenografts under conditions in which no significant change in immunostaining of the hypoxia marker pimonidazole had occurred. Methods and Materials: Gene expression profiles of volume-matched androgen-exposed and androgen-deprived CWR22 xenografts, with similar pimonidazole-positive fractions, were compared. Direct targets of androgen receptor (AR) and HIF1 transcription factors were identified among the differentially expressed genes by using published lists. Biological processes affected by ADT were determined by gene ontology analysis. HIF1α protein expression in xenografts and biopsy samples from 35 patients receiving neoadjuvant ADT was assessed by immunohistochemistry. Results: A total of 1344 genes showed more than 2-fold change in expression by ADT, including 35 downregulated and 5 upregulated HIF1 targets. Six genes were shared HIF1 and AR targets, and their downregulation was confirmed with quantitative RT-PCR. Significant suppression of the biological processes proliferation, metabolism, and stress response in androgen-deprived xenografts was found, consistent with tumor regression. Nineteen downregulated HIF1 targets were involved in those significant biological processes, most of them in metabolism. Four of these were shared AR and HIF1 targets, including genes encoding the regulatory glycolytic proteins HK2, PFKFB3, and SLC2A1. Most of the downregulated HIF1 targets were induced by hypoxia in androgen-responsive prostate cancer cell lines, confirming their role as hypoxia-responsive HIF1 targets in prostate cancer. Downregulation of HIF1 targets was consistent with the absence of HIF1α protein in xenografts and downregulation in patients by ADT (P<.001). Conclusions: AR repression by ADT may lead to downregulation of HIF1 signaling independently of hypoxic fraction, and this may contribute to

  16. Hypoxia-Independent Downregulation of Hypoxia-Inducible Factor 1 Targets by Androgen Deprivation Therapy in Prostate Cancer

    International Nuclear Information System (INIS)

    Ragnum, Harald Bull; Røe, Kathrine; Holm, Ruth; Vlatkovic, Ljiljana; Nesland, Jahn Marthin; Aarnes, Eva-Katrine; Ree, Anne Hansen; Flatmark, Kjersti; Seierstad, Therese; Lilleby, Wolfgang; Lyng, Heidi

    2013-01-01

    Purpose: We explored changes in hypoxia-inducible factor 1 (HIF1) signaling during androgen deprivation therapy (ADT) of androgen-sensitive prostate cancer xenografts under conditions in which no significant change in immunostaining of the hypoxia marker pimonidazole had occurred. Methods and Materials: Gene expression profiles of volume-matched androgen-exposed and androgen-deprived CWR22 xenografts, with similar pimonidazole-positive fractions, were compared. Direct targets of androgen receptor (AR) and HIF1 transcription factors were identified among the differentially expressed genes by using published lists. Biological processes affected by ADT were determined by gene ontology analysis. HIF1α protein expression in xenografts and biopsy samples from 35 patients receiving neoadjuvant ADT was assessed by immunohistochemistry. Results: A total of 1344 genes showed more than 2-fold change in expression by ADT, including 35 downregulated and 5 upregulated HIF1 targets. Six genes were shared HIF1 and AR targets, and their downregulation was confirmed with quantitative RT-PCR. Significant suppression of the biological processes proliferation, metabolism, and stress response in androgen-deprived xenografts was found, consistent with tumor regression. Nineteen downregulated HIF1 targets were involved in those significant biological processes, most of them in metabolism. Four of these were shared AR and HIF1 targets, including genes encoding the regulatory glycolytic proteins HK2, PFKFB3, and SLC2A1. Most of the downregulated HIF1 targets were induced by hypoxia in androgen-responsive prostate cancer cell lines, confirming their role as hypoxia-responsive HIF1 targets in prostate cancer. Downregulation of HIF1 targets was consistent with the absence of HIF1α protein in xenografts and downregulation in patients by ADT (P<.001). Conclusions: AR repression by ADT may lead to downregulation of HIF1 signaling independently of hypoxic fraction, and this may contribute to

  17. Characterization of the small RNA transcriptomes of androgen dependent and independent prostate cancer cell line by deep sequencing.

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    Gang Xu

    2010-11-01

    Full Text Available Given the important roles of miRNA in post-transcriptional regulation and its implications for cancer, characterization of miRNA facilitates us to uncover molecular mechanisms underlying the progression of androgen-independent prostate cancer (PCa. The emergence of next-generation sequencing technologies has dramatically changed the speed of all aspects of sequencing in a rapid and cost-effective fashion, which can permit an unbiased, quantitive and in-depth investigation of small RNA transcriptome. In this study, we used high-throughput Illumina sequencing to comprehensively represent the full complement of individual small RNA and to characterize miRNA expression profiles in both the androgen dependent and independent Pca cell line. At least 83 miRNAs are significantly differentially expressed, of which 41 are up-regulated and 42 are down-regulated, indicating these miRNAs may be involved in the transition of LNCaP to an androgen-independent phenotype. In addition, we have identified 43 novel miRNAs from the androgen dependent and independent PCa library and 3 of them are specific to the androgen-independent PCa. Function annotation of target genes indicated that most of these differentially expressed miRNAs tend to target genes involved in signal transduction and cell communication, epically the MAPK signaling pathway. The small RNA transcriptomes obtained in this study provide considerable insights into a better understanding of the expression and function of small RNAs in the development of androgen-independent prostate cancer.

  18. Histological changes caused by meclofenamic acid in androgen independent prostate cancer tumors: evaluation in a mouse model

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    Iván Delgado-Enciso

    2015-10-01

    Full Text Available ABSTRACT Meclofenamic acid is a nonsteroidal anti-inflammatory drug that has shown therapeutic potential for different types of cancers, including androgen-independent prostate neoplasms. The antitumor effect of diverse nonsteroidal anti-inflammatory drugs has been shown to be accompanied by histological and molecular changes that are responsible for this beneficial effect. The objective of the present work was to analyze the histological changes caused by meclofenamic acid in androgen-independent prostate cancer. Tumors were created in a nude mouse model using PC3 cancerous human cells. Meclofenamic acid (10 mg/kg/day; experimental group, n=5 or saline solution (control group, n=5 was administered intraperitoneally for twenty days. Histological analysis was then carried out on the tumors, describing changes in the cellular architecture, fibrosis, and quantification of cellular proliferation and tumor vasculature. Meclofenamic acid causes histological changes that indicate less tumor aggression (less hypercellularity, fewer atypical mitoses, and fewer nuclear polymorphisms, an increase in fibrosis, and reduced cellular proliferation and tumor vascularity. Further studies are needed to evaluate the molecular changes that cause the beneficial and therapeutic effects of meclofenamic acid in androgen-independent prostate cancer.

  19. Inhibition of Androgen-Independent Prostate Cancer by Estrogenic Compounds Is Associated with Increased Expression of Immune-Related Genes

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    Ilsa M. Coleman

    2006-10-01

    Full Text Available The clinical utility of estrogens for treating prostate cancer (CaP was established in the 1940s by Huggins. The classic model of the anti-CaP activity of estrogens postulates an indirect mechanism involving the suppression of androgen production. However, clinical, preclinical studies have shown that estrogens exert growth-inhibitory effects on CaP under low-androgen conditions, suggesting additional modes whereby estrogens affect CaP cells and/or the microenvironment. Here we have investigated the activity of 17β estradiol (E2 against androgen-independent CaP, identified molecular alterations in tumors exposed to E2. E2 treatment inhibited the growth of all four androgen-independent CaP xenografts studied (LuCaP 35V, LuCaP 23.1AI, LuCaP 49, LuCaP 58 in castrated male mice. The molecular basis of growth suppression was studied by cDNA microarray analysis, which indicated that multiple pathways are altered by E2 treatment. Of particular interest are changes in transcripts encoding proteins that mediate immune responses, regulate androgen receptor signaling. In conclusion, our data show that estrogens have powerful inhibitory effects on CaP in vivo in androgendepleted environments, suggest novel mechanisms of estrogen-mediated antitumor activity. These results indicate that incorporating estrogens into CaP treatment protocols could enhance therapeutic efficacy even in cases of advanced disease.

  20. Metabolic action of prolactin in regressing prostate: independent of androgen action

    International Nuclear Information System (INIS)

    Smith, C.; Assimos, D.; Lee, C.; Grayhack, J.T.

    1985-01-01

    The mechanism of the observed synergistic effect of prolactin and androgen on the lateral lobe of the rat prostate is not established. The observation that prolactin alone delayed the rate of loss of weight, protein, and DNA of the lateral lobe in castrated rats has led us to question the assumption that the effect of prolactin is produced by a modification of recognized androgen-induced intracellular changes. The present study was conducted to explore whether or not the sites of prolactin action in the rat prostate coincided with those recognized as the androgen effect. Two anterior pituitaries from female donors were grafted under the right renal capsule of adult male Sprague-Dawley rats. Seven days later, bilateral orchiectomy and unilateral nephrectomy were performed in these rats. In one half of the animals, the kidney bearing the pituitary grafts was removed. In the other half, the contralateral kidney was removed. Seven days following the orchiectomy-nephrectomy, animals bearing the pituitary grafts had a higher level of serum prolactin (93 +/- 7 ng/ml, mean +/- SE) than in those without the graft (26 +/- 3 ng/ml). This condition of hyperprolactinemia was associated with the delay of castration-induced regression in the lateral prostate. The rate of protein degradation, as judged by the amount of radioactivity remaining in the tissue following a single i.v. pulse of 3 H-leucine 24 hr before orchiectomy-nephrectomy, was significantly slower in the lateral prostate in graft-bearing animals than in those without grafts

  1. Co-Targeting Prostate Cancer Epithelium and Bone Stroma by Human Osteonectin-Promoter-Mediated Suicide Gene Therapy Effectively Inhibits Androgen-Independent Prostate Cancer Growth.

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    Shian-Ying Sung

    Full Text Available Stromal-epithelial interaction has been shown to promote local tumor growth and distant metastasis. We sought to create a promising gene therapy approach that co-targets cancer and its supporting stromal cells for combating castration-resistant prostate tumors. Herein, we demonstrated that human osteonectin is overexpressed in the prostate cancer epithelium and tumor stroma in comparison with their normal counterpart. We designed a novel human osteonectin promoter (hON-522E containing positive transcriptional regulatory elements identified in both the promoter and exon 1 region of the human osteonectin gene. In vitro reporter assays revealed that the hON-522E promoter is highly active in androgen receptor negative and metastatic prostate cancer and bone stromal cells compared to androgen receptor-positive prostate cancer cells. Moreover, in vivo prostate-tumor-promoting activity of the hON-522E promoter was confirmed by intravenous administration of an adenoviral vector containing the hON-522E promoter-driven luciferase gene (Ad-522E-Luc into mice bearing orthotopic human prostate tumor xenografts. In addition, an adenoviral vector with the hON-522E-promoter-driven herpes simplex virus thymidine kinase gene (Ad-522E-TK was highly effective against the growth of androgen-independent human prostate cancer PC3M and bone stromal cell line in vitro and in pre-established PC3M tumors in vivo upon addition of the prodrug ganciclovir. Because of the heterogeneity of human prostate tumors, hON-522E promoter-mediated gene therapy has the potential for the treatment of hormone refractory and bone metastatic prostate cancers.

  2. Phenotypic Plasticity, Bet-Hedging, and Androgen Independence in Prostate Cancer: Role of Non-Genetic Heterogeneity

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    Mohit Kumar Jolly

    2018-03-01

    Full Text Available It is well known that genetic mutations can drive drug resistance and lead to tumor relapse. Here, we focus on alternate mechanisms—those without mutations, such as phenotypic plasticity and stochastic cell-to-cell variability that can also evade drug attacks by giving rise to drug-tolerant persisters. The phenomenon of persistence has been well-studied in bacteria and has also recently garnered attention in cancer. We draw a parallel between bacterial persistence and resistance against androgen deprivation therapy in prostate cancer (PCa, the primary standard care for metastatic disease. We illustrate how phenotypic plasticity and consequent mutation-independent or non-genetic heterogeneity possibly driven by protein conformational dynamics can stochastically give rise to androgen independence in PCa, and suggest that dynamic phenotypic plasticity should be considered in devising therapeutic dosing strategies designed to treat and manage PCa.

  3. Wnt signaling promotes androgen-independent prostate cancer cell proliferation through up-regulation of the hippo pathway effector YAP.

    Science.gov (United States)

    Seo, Won Ik; Park, Seoyoung; Gwak, Jungsug; Ju, Bong Gun; Chung, Jae Il; Kang, Pil Moon; Oh, Sangtaek

    2017-05-13

    Aberrant up-regulation of Wnt/β-catenin signaling is associated with the development and progression of prostate cancer, but the underlying mechanism is unclear. Here we show that in the absence of androgens, the Wnt/β-catenin pathway activates AR-mediated transcription through up-regulation of the Hippo pathway effector Yes-associated protein (YAP). Wnt3a-conditioned medium (Wnt3a-CM) promotes the growth of LNCaP cells and increases AR and YAP protein levels. Moreover, Wnt3a-CM induces the nuclear translocation of YAP and the AR, but not β-catenin, thereby activating the expression of AR- and YAP-dependent genes, in an androgen-independent manner. In addition, depletion of YAP with small interfering RNA (siRNA) prevented Wnt3a-CM-mediated up-regulation of AR-dependent gene expression. Thus, our findings provide mechanistic insight into the proposed cross-talk between the Wnt/β-catenin and Hippo pathways in androgen-independent prostate cancer development. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Androgen and taxol cause cell type-specific alterations of centrosome and DNA organization in androgen-responsive LNCaP and androgen-independent DU145 prostate cancer cells

    Science.gov (United States)

    Schatten, H.; Ripple, M.; Balczon, R.; Weindruch, R.; Chakrabarti, A.; Taylor, M.; Hueser, C. N.

    2000-01-01

    We investigated the effects of androgen and taxol on the androgen-responsive LNCaP and androgen-independent DU145 prostate cancer cell lines. Cells were treated for 48 and 72 h with 0.05-1 nM of the synthetic androgen R1881 and with 100 nM taxol. Treatment of LNCaP cells with 0.05 nM R1881 led to increased cell proliferation, whereas treatment with 1 nM R1881 resulted in inhibited cell division, DNA cycle arrest, and altered centrosome organization. After treatment with 1 nM R1881, chromatin became clustered, nuclear envelopes convoluted, and mitochondria accumulated around the nucleus. Immunofluorescence microscopy with antibodies to centrosomes showed altered centrosome structure. Although centrosomes were closely associated with the nucleus in untreated cells, they dispersed into the cytoplasm after treatment with 1 nM R1881. Microtubules were only faintly detected in 1 nM R1881-treated LNCaP cells. The effects of taxol included microtubule bundling and altered mitochondria morphology, but not DNA organization. As expected, the androgen-independent prostate cancer cell line DU145 was not affected by R1881. Treatment with taxol resulted in bundling of microtubules in both cell lines. Additional taxol effects were seen in DU145 cells with micronucleation of DNA, an indication of apoptosis. Simultaneous treatment with R1881 and taxol had no additional effects on LNCaP or DU145 cells. These results suggest that LNCaP and DU145 prostate cancer cells show differences not only in androgen responsiveness but in sensitivity to taxol as well. Copyright 2000 Wiley-Liss, Inc.

  5. Phase I trial of yttrium-90-labeled anti-prostate-specific membrane antigen monoclonal antibody J591 for androgen-independent prostate cancer.

    Science.gov (United States)

    Milowsky, Matthew I; Nanus, David M; Kostakoglu, Lale; Vallabhajosula, Shankar; Goldsmith, Stanley J; Bander, Neil H

    2004-07-01

    To determine the maximum-tolerated dose (MTD), toxicity, human antihuman antibody (HAHA) response, pharmacokinetics, organ dosimetry, targeting, and preliminary efficacy of yttrium-90-labeled anti-prostate-specific membrane antigen monoclonal antibody J591 ((90)Y-J591) in patients with androgen-independent prostate cancer (PC). Patients with androgen-independent PC and evidence of disease progression received indium-111-J591 for pharmacokinetic and biodistribution determinations followed 1 week later by (90)Y-J591 at five dose levels: 5, 10, 15, 17.5, and 20 mCi/m(2). Patients were eligible for up to three re-treatments if platelet and neutrophil recovery was satisfactory. Twenty-nine patients with androgen-independent PC received (90)Y-J591, four of whom were re-treated. Dose limiting toxicity (DLT) was seen at 20 mCi/m(2), with two patients experiencing thrombocytopenia with non-life-threatening bleeding episodes requiring platelet transfusions. The 17.5-mCi/m(2) dose level was determined to be the MTD. No re-treated patients experienced DLT. Nonhematologic toxicity was not dose limiting. Targeting of known sites of bone and soft tissue metastases was seen in the majority of patients. No HAHA response was seen. Antitumor activity was seen, with two patients experiencing 85% and 70% declines in prostate-specific antigen (PSA) levels lasting 8 and 8.6 months, respectively, before returning to baseline. Both patients had objective measurable disease responses. An additional six patients (21%) experienced PSA stabilization. The recommended dose for (90)Y-J591 is 17.5 mCi/m(2). Acceptable toxicity, excellent targeting of known sites of PC metastases, and biologic activity in patients with androgen-independent PC warrant further investigation of (90)Y-J591 in the treatment of patients with PC.

  6. Androgen-independent effects of Serenoa repens extract (Prostasan®) on prostatic epithelial cell proliferation and inflammation

    DEFF Research Database (Denmark)

    Iglesias-Gato, Diego; Carsten, Tober; Vesterlund, Mattias

    2012-01-01

    . Prostasan® inhibited epidermal growth factor (EGF) and lipopolysaccharide (LPS) induced proliferation of the prostatic epithelial, androgen independent cell line PC-3. At effective concentrations of 50 µg/mL, Prostasan® partly displaced EGF from EGF receptor (EGFR) but fully blocked EGF-induced cell...... proliferation of PC-3 cells. Similarly, Prostasan® inhibited LPS-induced proliferation of PC-3 cells without affecting LPS activation of the NFĸB pathway via toll-like receptor-4 (TLR-4). Additionally, Prostasan® reduced the constitutive secretion of monocyte chemotactic protein-1 (MCP-1), the LPS......-induced secretion of IL-12 and inhibited MCP-1 and granulocyte-macrophage colony-stimulating factor (GM-CSF) production in the presence of LPS on PC-3 cells. Taken together, our results suggest that S. repens extracts, in addition to other reported effects on BPH development and prostatitis, inhibits EGF...

  7. p38MAPK activation is involved in androgen-independent proliferation of human prostate cancer cells by regulating IL-6 secretion

    International Nuclear Information System (INIS)

    Shida, Yohei; Igawa, Tsukasa; Hakariya, Tomoaki; Sakai, Hideki; Kanetake, Hiroshi

    2007-01-01

    Increased levels of serum interleukin-6 (IL-6) are frequently observed in patients with advanced, hormone-refractory prostate cancer. However, the precise mechanism of IL-6 regulation is still largely unknown. Since prostate cancer gradually progresses to an androgen-independent state despite the stress caused by various therapeutic agents, we hypothesized the stress-activated protein kinases (SAPKs) involvement in androgen-independent growth or IL-6 secretion of prostate cancer cells. Using PC-3 and DU145 human prostate cancer cells, we analyzed the role of SAPKs in IL-6 mediated cell growth and found that the p38MAPK and JNK are involved in androgen-independent cancer cell growth. Furthermore, IL-6 secretion by PC-3 and DU145 cells was significantly suppressed by SAPKs inhibitor, especially by p38MAPK inhibitor SB203580, but not by JNK inhibitor SP600125 nor by MEK inhibitor, PD98059. These results raised the possibility that the IL-6 mediated androgen-independent proliferation of PC-3 and DU145 cells is regulated at least partly via SAPKs signaling pathway especially through p38MAPK activation

  8. Increased expression of heparin binding EGF (HB-EGF), amphiregulin, TGF alpha and epiregulin in androgen-independent prostate cancer cell lines.

    DEFF Research Database (Denmark)

    Tørring, Niels; Sørensen, Boe Sandahl; Nexø, Ebba

    2000-01-01

    BACKGROUND: The proliferation of androgen-independent prostate cancer cell lines has previously been shown to be influenced by an autocrine loop of the epidermal growth factor (EGF) system. This observation has alerted us to study the expression of ligands and receptors from the EGF-system in pro...

  9. Inhibition of Androgen-Independent Growth of Prostate Cancer by siRNA- Mediated Androgen Receptor Gene Silencing

    Science.gov (United States)

    2008-02-01

    mediated shift of Bcl-x pre-mRNA splicing and antineoplastic agents. J Biol Chem 2002;277:49374–82. 39. Wright ME, Tsai MJ, Aebersold R. Androgen receptor...two orders of magnitude better than nanowire arrays, but these assays require extensive labeling and mul- tiple chemical and biochemical manipulations

  10. The Role of AKT in Androgen-Independent Progression of Human Prostate Cancer

    Science.gov (United States)

    2005-02-01

    androgen ablation (2). However, there has been a growing appreciation that most patients treated by androgen ablation ultimately relapse to more aggressive...activation. (c) Bicistronic vector, iAkt,., containing M-FRB12 and F3-APH.Akt separated by the poliovirus IRES, functions more efficiently than iAkt...characterized IRES from poliovirus . Following specific antibodies against Akt S473 and T308 sites as electroporation of bicistronic vectors into Jurkat

  11. Preparation of nanobubbles carrying androgen receptor siRNA and their inhibitory effects on androgen-independent prostate cancer when combined with ultrasonic irradiation.

    Directory of Open Access Journals (Sweden)

    Luofu Wang

    Full Text Available OBJECTIVE: The objective of this study was to investigate nanobubbles carrying androgen receptor (AR siRNA and their in vitro and in vivo anti-tumor effects, when combined with ultrasonic irradiation, on androgen-independent prostate cancer (AIPC. MATERIALS AND METHODS: Nanobubbles carrying AR siRNA were prepared using poly-L-lysine and electrostatic adsorption methods. Using C4-2 cell activity as a testing index, the optimal irradiation parameters (including the nanobubble number/cell number ratio, mechanical index [MI], and irradiation time were determined and used for transfection of three human prostate cancer cell lines (C4-2, LNCaP, and PC-3 cells. The AR expression levels were investigated with RT-PCR and Western blot analysis. Additionally, the effects of the nanobubbles and control microbubbles named SonoVue were assessed via imaging in a C4-2 xenograft model. Finally, the growth and AR expression of seven groups of tumor tissues were assessed using the C4-2 xenograft mouse model. RESULTS: The nanobubbles had an average diameter of 609.5±15.6 nm and could effectively bind to AR siRNA. Under the optimized conditions of a nanobubble number/cell number ratio of 100∶1, an MI of 1.2, and an irradiation time of 2 min, the highest transfection rates in C4-2, LNCaP, and PC-3 cells were 67.4%, 74.0%, and 63.96%, respectively. In the C4-2 and LNCaP cells, treatment with these binding nanobubbles plus ultrasonic irradiation significantly inhibited cell growth and resulted in the suppression of AR mRNA and protein expression. Additionally, contrast-enhanced ultrasound showed that the nanobubbles achieved stronger signals than the SonoVue control in the central hypovascular area of the tumors. Finally, the anti-tumor effect of these nanobubbles plus ultrasonic irradiation was most significant in the xenograft tumor model compared with the other groups. CONCLUSION: Nanobubbles carrying AR siRNA could be potentially used as gene vectors in

  12. Natural proteasome inhibitor celastrol suppresses androgen-independent prostate cancer progression by modulating apoptotic proteins and NF-kappaB.

    Directory of Open Access Journals (Sweden)

    Yao Dai

    Full Text Available Celastrol is a natural proteasome inhibitor that exhibits promising anti-tumor effects in human malignancies, especially the androgen-independent prostate cancer (AIPC with constitutive NF-κB activation. Celastrol induces apoptosis by means of proteasome inhibition and suppresses prostate tumor growth. However, the detailed mechanism of action remains elusive. In the current study, we aim to test the hypothesis that celastrol suppresses AIPC progression via inhibiting the constitutive NF-κB activity as well as modulating the Bcl-2 family proteins.We examined the efficacy of celastrol both in vitro and in vivo, and evaluated the role of NF-κB in celastrol-mediated AIPC regression. We found that celastrol inhibited cell proliferation in all three AIPC cell lines (PC-3, DU145 and CL1, with IC₅₀ in the range of 1-2 µM. Celastrol also suppressed cell migration and invasion. Celastrol significantly induced apoptosis as evidenced by increased sub-G1 population, caspase activation and PARP cleavage. Moreover, celastrol promoted cleavage of the anti-apoptotic protein Mcl-1 and activated the pro-apoptotic protein Noxa. In addition, celastrol rapidly blocked cytosolic IκBα degradation and nuclear translocation of RelA. Likewise, celastrol inhibited the expression of multiple NF-κB target genes that are involved in proliferation, invasion and anti-apoptosis. Celastrol suppressed AIPC tumor progression by inhibiting proliferation, increasing apoptosis and decreasing angiogenesis, in PC-3 xenograft model in nude mouse. Furthermore, increased cellular IκBα and inhibited expression of various NF-κB target genes were observed in tumor tissues.Our data suggest that, via targeting the proteasome, celastrol suppresses proliferation, invasion and angiogenesis by inducing the apoptotic machinery and attenuating constitutive NF-κB activity in AIPC both in vitro and in vivo. Celastrol as an active ingredient of traditional herbal medicine could thus be

  13. Detection of bony metastases of androgen-independent prostate cancer by PET-FDG

    International Nuclear Information System (INIS)

    Yeh, Samuel D. J.; Imbriaco, Massimo; Larson, Steven M.; Garza, Dahlia; Zhang Jiaju; Kalaigian, Hovanes; Finn, Ronald D.; Reddy, David; Horowitz, Steven M.; Goldsmith, Stanley J.; Scher, Howard I.

    1996-01-01

    Fourteen F-18 fluorodeoxyglucose (FDG) studies were carried out in 13 patients known to have bony metastases from carcinoma of the prostate. One patient was newly diagnosed. The remaining patients had various types of therapy and were considered hormonally resistant. The average age was 67. All patients had extensive bony metastases shown on the conventional Tc99m-MDP bone scans. Only about 18% of bony lesions apparent on the conventional bone scans showed corresponding increase of FDG uptake. Anatomical correlation was performed by using co-registered images of SPECT and PET in the same area. The positive FDG uptake was not related to the duration of illness, level of PSA, previous therapy, and magnitude of disease involvement. It appears that only a small percentage of bony metastases is associated with increased glycolysis. It is possible that other metabolic processes are more important than glycolysis for providing prostate cancer with a source of energy and nutrients

  14. Detection of bony metastases of androgen-independent prostate cancer by PET-FDG

    Energy Technology Data Exchange (ETDEWEB)

    Yeh, Samuel D. J.; Imbriaco, Massimo; Larson, Steven M.; Garza, Dahlia; Zhang Jiaju; Kalaigian, Hovanes; Finn, Ronald D.; Reddy, David; Horowitz, Steven M.; Goldsmith, Stanley J.; Scher, Howard I

    1996-08-01

    Fourteen F-18 fluorodeoxyglucose (FDG) studies were carried out in 13 patients known to have bony metastases from carcinoma of the prostate. One patient was newly diagnosed. The remaining patients had various types of therapy and were considered hormonally resistant. The average age was 67. All patients had extensive bony metastases shown on the conventional Tc99m-MDP bone scans. Only about 18% of bony lesions apparent on the conventional bone scans showed corresponding increase of FDG uptake. Anatomical correlation was performed by using co-registered images of SPECT and PET in the same area. The positive FDG uptake was not related to the duration of illness, level of PSA, previous therapy, and magnitude of disease involvement. It appears that only a small percentage of bony metastases is associated with increased glycolysis. It is possible that other metabolic processes are more important than glycolysis for providing prostate cancer with a source of energy and nutrients.

  15. Evaluation of Roles of Interferon Gamma Regulated Genes in Inhibition of Androgen-Independent Prostate Cancer

    Science.gov (United States)

    2006-08-01

    glucose phosphate isomerase AI124792 2821 -1.8 RPN1 ribophorin I CD644128 6184 -1.8 AR SORD sorbitol dehydrogenase BC025295 6652 -1.6 AR GRHPR...identification of active principles. J Natl Cancer Inst 2002; 94: 1275-81. [151] Thomson JO, Dzubak P, Hajduch M. Prostate cancer and the food ...METABOLISM METABOLISM - CARBOHYDRATE UGDH UDP- glucose dehydrogenase BC022781 7358 -2.0 GALNT7 UDP-N-acetyl-alpha-D-galactosamine BM976847 51809 -1.8 GPI

  16. Regulation of Androgen Responses in Prostate Cancer by BAG-1

    National Research Council Canada - National Science Library

    Reed, John

    2001-01-01

    .... However, nearly all tumors eventually relapse as hormone-refractory disease. A need therefore exists for better understanding of the mechanisms that allow prostate cancer cells to grow in an androgen - independent manner...

  17. Regulation of Androgen Responses in Prostate Cancer by BAG-1

    National Research Council Canada - National Science Library

    Reed, John

    1999-01-01

    .... However, nearly all tumors eventually relapse as hormone- refractory disease. A need therefore exists for better understanding of the mechanisms that allow prostate cancer cells to grow in an androgen - independent manner...

  18. Androgen regulation of prostate cancer: where are we now?

    Science.gov (United States)

    Corona, G; Baldi, E; Maggi, M

    2011-03-01

    Androgens play an essential role in the development and differentiation of the prostate gland; their contribution to pathological conditions, such as benign prostatic hyperplasia and prostate cancer (PC), remains unclear. We reviewed relationships between androgens and the prostate both in physiological and pathological conditions. A systematic search of published evidence was performed using Medline (1969 to September 2010). Androgen-dependency of prostate growth is evident only in the hypogonadal condition, but not in the eugonadal state (the "saturation hypothesis"). There is unequivocal evidence that reducing androgen signaling to the hypogonadal range can reduce PC growth and patient symptoms. At physiological testosterone concentration there is no link between androgen levels and PC risk. In addition, different strategies of androgen deprivation (ADT) for advanced PC are only palliative and rarely cure patients. Preliminary evidence indicates that a low androgen milieu is associated with tumor aggressiveness. Transition to androgen-independence is complex and involves both selection and outgrowth of preexisting androgen resistant clones, as well as adaptative upregulation of genes that help the cancer cells to survive and grow after ADT. Because androgens are essential for the regulation of fat distribution, insulin sensitivity, and lipid and bone metabolism, recent publications have highlighted the concept that ADT may also be involved with an increase in overall, as well as cardiovascular, morbidity and mortality. While ADT still represents a cornerstone for the palliative therapy of a small fraction of aggressive PC, a "misuse and/or abuse" of ADT should be avoided.

  19. Androgen receptor signaling is required for androgen-sensitive human prostate cancer cell proliferation and survival

    Directory of Open Access Journals (Sweden)

    Day Wanda V

    2005-04-01

    Full Text Available Abstract Background Androgens and androgen receptors (AR regulate normal prostate development and growth. They also are involved in pathological development of prostatic diseases, including benign prostatic hyperplasia (BPH and prostate cancer (PCa. Antiandrogen therapy for PCa, in conjunction with chemical or surgical castration, offers initial positive responses and leads to massive prostate cell death. However, cancer cells later appear as androgen-independent PCa. To investigate the role of AR in prostate cell proliferation and survival, we introduced a vector-based small interfering RNA (siRNA. This siRNA targeted 5'-untranslated region of AR mRNA for extended suppression of AR expression in androgen-sensitive human prostate LNCaP cells. Results The siRNA design successfully suppressed endogenous AR expression, as revealed by western blotting and immunofluorescence staining in LNCaP cells. LNCaP cells did not proliferate in the absence of AR and underwent apoptosis, based on elevated phospho-Histone H2B expression and higher number of apoptotic body as compared to control cells. Conclusion We demonstrated that AR is vital for prostate cell proliferation and survival in this androgen-sensitive prostate cell line. These results further strengthen the hypothesis that AR can be a therapeutic target for treating androgen-sensitive stages of PCa. Unlike antiandorgens, however, siRNA targeting AR provides a direct inactivation of AR function through the suppression of AR protein expression.

  20. Withaferin A Induces Cell Death Selectively in Androgen-Independent Prostate Cancer Cells but Not in Normal Fibroblast Cells.

    Directory of Open Access Journals (Sweden)

    Yukihiro Nishikawa

    Full Text Available Withaferin A (WA, a major bioactive component of the Indian herb Withania somnifera, induces cell death (apoptosis/necrosis in multiple types of tumor cells, but the molecular mechanism underlying this cytotoxicity remains elusive. We report here that 2 μM WA induced cell death selectively in androgen-insensitive PC-3 and DU-145 prostate adenocarcinoma cells, whereas its toxicity was less severe in androgen-sensitive LNCaP prostate adenocarcinoma cells and normal human fibroblasts (TIG-1 and KD. WA also killed PC-3 cells in spheroid-forming medium. DNA microarray analysis revealed that WA significantly increased mRNA levels of c-Fos and 11 heat-shock proteins (HSPs in PC-3 and DU-145, but not in LNCaP and TIG-1. Western analysis revealed increased expression of c-Fos and reduced expression of the anti-apoptotic protein c-FLIP(L. Expression of HSPs such as HSPA6 and Hsp70 was conspicuously elevated; however, because siRNA-mediated depletion of HSF-1, an HSP-inducing transcription factor, reduced PC-3 cell viability, it is likely that these heat-shock genes were involved in protecting against cell death. Moreover, WA induced generation of reactive oxygen species (ROS in PC-3 and DU-145, but not in normal fibroblasts. Immunocytochemistry and immuno-electron microscopy revealed that WA disrupted the vimentin cytoskeleton, possibly inducing the ROS generation, c-Fos expression and c-FLIP(L suppression. These observations suggest that multiple events followed by disruption of the vimentin cytoskeleton play pivotal roles in WA-mediated cell death.

  1. Activation of estrogen receptor beta (ERβ) regulates the expression of N-cadherin, E-cadherin and β-catenin in androgen-independent prostate cancer cells.

    Science.gov (United States)

    Silva, Rafael de Souza; Lombardi, Ana Paola G; de Souza, Deborah Simão; Vicente, Carolina M; Porto, Catarina S

    2018-03-01

    The aim of the present study was to investigate the impact of the activation of estrogen receptors on expression and localization of N-cadherin, E-cadherin and non-phosphorylated β-catenin in androgen-independent prostate cancer cells (PC-3 and DU-145) and in human post pubertal prostate epithelial cells (PNT1A). Expression of N-cadherin was detected in PNT1A and PC-3 cells, but not in DU-145 cells. E-cadherin was detected only in DU-145 cells and β-catenin was detected in all cells studied. N-cadherin and β-catenin were located preferentially in the cellular membrane of PNT1A cells and in the cytoplasm of PC-3 cells. E-cadherin and β-catenin were located preferentially in the cellular membrane of DU-145 cells. 17β-estradiol (E2) or the ERα-selective agonist PPT did not affect the content and localization of N-cadherin in PC-3 and PNT1A cells or E-cadherin in DU-145 cells. In PC-3 cells, ERβ-selective agonist DPN decreased the expression of N-cadherin. DPN-induced downregulation of N-cadherin was blocked by pretreatment with the ERβ-selective antagonist (PHTPP), indicating that ERβ1 is the upstream receptor regulating the expression of N-cadherin. In DU-145 cells, the activation of ERβ1 by DPN increased the expression of E-cadherin. Taken together, these results suggest that activation of ERβ1 is required to maintain an epithelial phenotype in PC-3 and DU-145 cells. The activation of ERβ1 also increased the expression of β-catenin in cytoplasm of PC-3 and in the cellular membrane of DU-145 cells. In conclusion, our results indicate differential expression and localization of N-cadherin, E-cadherin and β-catenin in androgen-independent prostate cancer cells. The reduction of N-cadherin content by activation of ERβ, exclusively observed in androgen-independent prostate cancer cells (PC-3), may be related to the activation of signaling pathways, such as the release of β-catenin into the cytoplasm, translocation of β-catenin to the nucleus and

  2. Microwave mediated radiosynthesis of [F-18] FLT and its in-vitro study with androgen independent human prostate cancer cell line (PC-3)

    International Nuclear Information System (INIS)

    Ponde, D.E.; Dence, C.S.; Oyama, N.; Welch, M.J.

    2003-01-01

    The aim of this work was to improve the radiosynthesis of [F-18] FLT and to study its usefulness in monitoring change of proliferative activity of prostate cancer cells in the early phase of therapy. Method: Starting with anhydrothymidine, [F-18] FLT was synthesized by microwave mediated nucleophilic displacement by fluoride ion followed by acid hydrolysis in a synthesis time of just 55 minutes, which included Oasis solid phase and HPLC purification. The total radiochemical yield was 10-15% (at EOS), and the radiochemical purity was >99%. An in vitro study was carried out with androgen-independent human prostate cancer cell line PC-3. Two X 10e5 cells were seeded in 6 well plates with Ham's F-12K medium with 2 mM L-glutamine adjusted to contain 1.5 g/L sodium bicarbonate supplemented with 10% heat activated FBS. One day later, PC-3 cells were at 50% confluent, the media was removed and the cells divided into two groups. In one group, cells were suspended in fresh media as above with 10% FBS, whereas in the other group cells were suspended in fresh media as above but without serum. Twenty-four hours later, [F-18] FLT was added to each flask (n=3). The cell-associated uptake of [F-18] FLT at 37 deg C was determined at 0, 1, 3, and 6 h after incubation. [F-18] FLT uptake in PC-3 cells decreased by 55% (from 9% to 4%) after 24h incubation with serum free media, indicating its potential usefulness to monitor cell proliferation in androgen-independent human prostate cancer. Studies to ascertain the uptake-mechanism are in the way. NIH grant HL13851

  3. Antioxidants Abrogate Alpha-Tocopherylquinone-Mediated Down-Regulation of the Androgen Receptor in Androgen-Responsive Prostate Cancer Cells.

    Directory of Open Access Journals (Sweden)

    Alexandra M Fajardo

    Full Text Available Tocopherylquinone (TQ, the oxidation product of alpha-tocopherol (AT, is a bioactive molecule with distinct properties from AT. In this study, AT and TQ are investigated for their comparative effects on growth and androgenic activity in prostate cancer cells. TQ potently inhibited the growth of androgen-responsive prostate cancer cell lines (e.g., LAPC4 and LNCaP cells, whereas the growth of androgen-independent prostate cancer cells (e.g., DU145 cells was not affected by TQ. Due to the growth inhibitory effects induced by TQ on androgen-responsive cells, the anti-androgenic properties of TQ were examined. TQ inhibited the androgen-induced activation of an androgen-responsive reporter and inhibited the release of prostate specific antigen from LNCaP cells. TQ pretreatment was also found to inhibit AR activation as measured using the Multifunctional Androgen Receptor Screening assay. Furthermore, TQ decreased androgen-responsive gene expression, including TM4SF1, KLK2, and PSA over 5-fold, whereas AT did not affect the expression of androgen-responsive genes. Of importance, the antiandrogenic effects of TQ on prostate cancer cells were found to result from androgen receptor protein down-regulation produced by TQ that was not observed with AT treatment. Moreover, none of the androgenic endpoints assessed were affected by AT. The down-regulation of androgen receptor protein by TQ was abrogated by co-treatment with antioxidants. Overall, the biological actions of TQ were found to be distinct from AT, where TQ was found to be a potent inhibitor of cell growth and androgenic activity in androgen-responsive prostate cancer cells.

  4. Influence of obesity and androgen deficiency on prostatic blood circulation

    Directory of Open Access Journals (Sweden)

    I. A. Tyuzikov

    2012-01-01

    Full Text Available In Study at 120 Diabetes Mellitus II type men the high frequency Obesity (71,7% and Androgen Deficiency (52,8—64,5% of the patients depending on a degree of the indemnification and them pathogenic authentic communications were shown. The blood level of total testosterone was represented by the critical factor of Prostatic arterial Blood Circulation. Obesity and Androgen Deficiency are seem as independent risk factors to development of ischemic prostatopathy, such as Prostatic blood circulation Disorders can develop earlier than other variants of the diabetic microangiophaty.

  5. Androgens and androgen receptors in prostatic cancer

    NARCIS (Netherlands)

    O.G.J.M. van Aubel (Olav)

    1989-01-01

    textabstractOur understanding of the testicular control of growth and functioning of the accessory sex glands began with an observation in the 18th century of John Hunter (1), who discovered in animals the endocrine dependency of the prostate. He demonstrated that castration in experimental

  6. Cyproterone acetate enhances TRAIL-induced androgen-independent prostate cancer cell apoptosis via up-regulation of death receptor 5.

    Science.gov (United States)

    Chen, Linjie; Wolff, Dennis W; Xie, Yan; Lin, Ming-Fong; Tu, Yaping

    2017-03-07

    Virtually all prostate cancer deaths occur due to obtaining the castration-resistant phenotype after prostate cancer cells escaped from apoptosis and/or growth suppression initially induced by androgen receptor blockade. TNF-related apoptosis-inducing ligand (TRAIL) was an attractive cancer therapeutic agent due to its minimal toxicity to normal cells and remarkable apoptotic activity in tumor cells. However, most localized cancers including prostate cancer are resistant to TRAIL-induced apoptosis, thereby creating a therapeutic challenge of inducing TRAIL sensitivity in cancer cells. Herein the effects of cyproterone acetate, an antiandrogen steroid, on the TRAIL-induced apoptosis of androgen receptor-negative prostate cancer cells are reported. Cell apoptosis was assessed by both annexin V/propidium iodide labeling and poly (ADP-ribose) polymerase cleavage assays. Gene and protein expression changes were determined by quantitative real-time PCR and western blot assays. The effect of cyproterone acetate on gene promoter activity was determined by luciferase reporter assay. Cyproterone acetate but not AR antagonist bicalutamide dramatically increased the susceptibility of androgen receptor-negative human prostate cancer PC-3 and DU145 cells to TRAIL-induced apoptosis but no effects on immortalized human prostate stromal PS30 cells and human embryonic kidney HEK293 cells. Further investigation of the TRAIL-induced apoptosis pathway revealed that cyproterone acetate exerted its effect by selectively increasing death receptor 5 (DR5) mRNA and protein expression. Cyproterone acetate treatment also increased DR5 gene promoter activity, which could be abolished by mutation of a consensus binding domain of transcription factor CCAAT-enhancer-binding protein homologous protein (CHOP) in the DR5 gene promoter. Cyproterone acetate increases CHOP expression in a concentration and time-dependent manner and endoplasmic reticulum stress reducer 4-phenylbutyrate could block

  7. Arylisothiocyanato selective androgen receptor modulators (SARMs) for prostate cancer.

    Science.gov (United States)

    Hwang, Dong Jin; Yang, Jun; Xu, Huiping; Rakov, Igor M; Mohler, Michael L; Dalton, James T; Miller, Duane D

    2006-10-01

    A new series of androgen receptor targeted agents (ARTA) was prepared and tested in androgen-dependent and -independent prostate cancer cell lines. These agents were bicalutamide analogs with isothiocyanato substituted B-rings. Also, the linker sulfone of R-bicalutamide was maintained or replaced with several alternative linkages including ether, amine, N-methylamine, thioether, and methylene (in this case the product was a racemic mixture) functional groups at the X-position. To expand the structure-activity relationship (SAR) of these arylisothiocyanato AR ligands, B-ring halogenated arylisothiocyanato ligands were also prepared and tested. The arylisothiocyanato AR ligands showed strong binding affinities to AR ranging from 0.6 to 54 nM. Among them, thioether and ether linkages demonstrated high binding affinities (0.6 and 4.6 nM, respectively) and selective cell growth inhibition (approximately 3- to 6-fold) for LNCaP, an androgen-dependent prostate cancer cell line, when compared to the androgen independent prostate cell lines (DU145, PC-3, and PPC-1) and a bladder cell line (TSU-Pr1). However, the ligands were inactive (IC50>100 mM) in a normal monkey kidney cell line (CV-1) that was used as the control for non-specific toxicity.

  8. Nutritional Effect on Androgen-Response Gene Expression and Prostate Tumor Growth

    National Research Council Canada - National Science Library

    Wang, Zhou

    2001-01-01

    ... (T) and dihydrotestosterone (DHT), and intraprostatic T and DHT in experimental animals. Thus, high fat diet is likely to modulate the ventral prostate weight via an androgen-independent mechanism...

  9. Transfected poly(I:C) activates different dsRNA receptors, leading to apoptosis or immunoadjuvant response in androgen-independent prostate cancer cells.

    Science.gov (United States)

    Palchetti, Sara; Starace, Donatella; De Cesaris, Paola; Filippini, Antonio; Ziparo, Elio; Riccioli, Anna

    2015-02-27

    Despite the effectiveness of surgery or radiation therapy for the treatment of early-stage prostate cancer (PCa), there is currently no effective strategy for late-stage disease. New therapeutic targets are emerging; in particular, dsRNA receptors Toll-like receptor 3 (TLR3) and cytosolic helicases expressed by cancer cells, once activated, exert a pro-apoptotic effect in different tumors. We previously demonstrated that the synthetic analog of dsRNA poly(I:C) induces apoptosis in the androgen-dependent PCa cell line LNCaP in a TLR3-dependent fashion, whereas only a weak apoptotic effect is observed in the more aggressive and androgen-independent PCa cells PC3 and DU145. In this paper, we characterize the receptors and the signaling pathways involved in the remarkable apoptosis induced by poly(I:C) transfected by Lipofectamine (in-poly(I:C)) compared with the 12-fold higher free poly(I:C) concentration in PC3 and DU145 cells. By using genetic inhibition of different poly(I:C) receptors, we demonstrate the crucial role of TLR3 and Src in in-poly(I:C)-induced apoptosis. Therefore, we show that the increased in-poly(I:C) apoptotic efficacy is due to a higher binding of endosomal TLR3. On the other hand, we show that in-poly(I:C) binding to cytosolic receptors MDA5 and RIG-I triggers IRF3-mediated signaling, leading uniquely to the up-regulation of IFN-β, which likely in turn induces increased TLR3, MDA5, and RIG-I proteins. In summary, in-poly(I:C) activates two distinct antitumor pathways in PC3 and DU145 cells: one mediated by the TLR3/Src/STAT1 axis, leading to apoptosis, and the other one mediated by MDA5/RIG-I/IRF3, leading to immunoadjuvant IFN-β expression. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  10. Proteasomal degradation of sphingosine kinase 1 and inhibition of dihydroceramide desaturase by the sphingosine kinase inhibitors, SKi or ABC294640, induces growth arrest in androgen-independent LNCaP-AI prostate cancer cells.

    Science.gov (United States)

    McNaughton, Melissa; Pitman, Melissa; Pitson, Stuart M; Pyne, Nigel J; Pyne, Susan

    2016-03-29

    Sphingosine kinases (two isoforms termed SK1 and SK2) catalyse the formation of the bioactive lipid sphingosine 1-phosphate. We demonstrate here that the SK2 inhibitor, ABC294640 (3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide) or the SK1/SK2 inhibitor, SKi (2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole)) induce the proteasomal degradation of SK1a (Mr = 42 kDa) and inhibit DNA synthesis in androgen-independent LNCaP-AI prostate cancer cells. These effects are recapitulated by the dihydroceramide desaturase (Des1) inhibitor, fenretinide. Moreover, SKi or ABC294640 reduce Des1 activity in Jurkat cells and ABC294640 induces the proteasomal degradation of Des1 (Mr = 38 kDa) in LNCaP-AI prostate cancer cells. Furthermore, SKi or ABC294640 or fenretinide increase the expression of the senescence markers, p53 and p21 in LNCaP-AI prostate cancer cells. The siRNA knockdown of SK1 or SK2 failed to increase p53 and p21 expression, but the former did reduce DNA synthesis in LNCaP-AI prostate cancer cells. Moreover, N-acetylcysteine (reactive oxygen species scavenger) blocked the SK inhibitor-induced increase in p21 and p53 expression but had no effect on the proteasomal degradation of SK1a. In addition, siRNA knockdown of Des1 increased p53 expression while a combination of Des1/SK1 siRNA increased the expression of p21. Therefore, Des1 and SK1 participate in regulating LNCaP-AI prostate cancer cell growth and this involves p53/p21-dependent and -independent pathways. Therefore, we propose targeting androgen-independent prostate cancer cells with compounds that affect Des1/SK1 to modulate both de novo and sphingolipid rheostat pathways in order to induce growth arrest.

  11. Sphingosine kinase-1 is central to androgen-regulated prostate cancer growth and survival.

    Directory of Open Access Journals (Sweden)

    Audrey Dayon

    Full Text Available BACKGROUND: Sphingosine kinase-1 (SphK1 is an oncogenic lipid kinase notably involved in response to anticancer therapies in prostate cancer. Androgens regulate prostate cancer cell proliferation, and androgen deprivation therapy is the standard of care in the management of patients with advanced disease. Here, we explored the role of SphK1 in the regulation of androgen-dependent prostate cancer cell growth and survival. METHODOLOGY/PRINCIPAL FINDINGS: Short-term androgen removal induced a rapid and transient SphK1 inhibition associated with a reduced cell growth in vitro and in vivo, an event that was not observed in the hormono-insensitive PC-3 cells. Supporting the critical role of SphK1 inhibition in the rapid effect of androgen depletion, its overexpression could impair the cell growth decrease. Similarly, the addition of dihydrotestosterone (DHT to androgen-deprived LNCaP cells re-established cell proliferation, through an androgen receptor/PI3K/Akt dependent stimulation of SphK1, and inhibition of SphK1 could markedly impede the effects of DHT. Conversely, long-term removal of androgen support in LNCaP and C4-2B cells resulted in a progressive increase in SphK1 expression and activity throughout the progression to androgen-independence state, which was characterized by the acquisition of a neuroendocrine (NE-like cell phenotype. Importantly, inhibition of the PI3K/Akt pathway--by negatively impacting SphK1 activity--could prevent NE differentiation in both cell models, an event that could be mimicked by SphK1 inhibitors. Fascinatingly, the reversability of the NE phenotype by exposure to normal medium was linked with a pronounced inhibition of SphK1 activity. CONCLUSIONS/SIGNIFICANCE: We report the first evidence that androgen deprivation induces a differential effect on SphK1 activity in hormone-sensitive prostate cancer cell models. These results also suggest that SphK1 activation upon chronic androgen deprivation may serve as a

  12. New insights into the androgen biotransformation in prostate cancer: A regulatory network among androgen, androgen receptors and UGTs.

    Science.gov (United States)

    Qin, Xuan; Liu, Mingyao; Wang, Xin

    2016-04-01

    Androgen, as one kind of steroid hormones, is pivotal in the hormone-sensitive cancer, such as prostate cancer (PCa). The synthesis, elimination, and bioavailability of androgen in prostate cells have been proved to be a main cause of the carcinogenesis, maintenance and deterioration of PCa. This review illustrates the outlines of androgen biotransformation, and further discusses the different enzymes, especially UDP-glucuronyltransferases (UGTs) embedded in both benign and malignant prostate cells, which catalyze the reactions. Although many inhibitors of the enzymes responsible for the synthesis of androgens have been developed into drugs to fight against PCa, the elimination procedures metabolized by the UGTs are less emphasized. Thus the regulatory network among androgen, androgen receptors (AR) and UGTs is carefully reviewed in this article, indicating the determinant effects of UGTs on prostatic androgens and the regulation of AR. Finally, the hypothesis is also put forward that the regulators of UGTs may be developed to accelerate the androgen elimination and benefit PCa therapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Androgen Receptor Mutations and Polymorphisms in African American Prostate Cancer

    OpenAIRE

    Koochekpour, Shahriar; Buckles, Erick; Shourideh, Mojgan; Hu, SiYi; Chandra, Dhyan; Zabaleta, Jovanny; Attwood, Kristopher

    2014-01-01

    The Androgen receptor (AR) plays a central role in the normal development of the prostate gland, in prostate carcinogenesis, and in the progression of prostate cancer (PCa) to advanced metastatic disease. African American (AA) men with PCa present with higher tumor volume, more advanced tumor stage, and higher Gleason score. This could be in part related to the AR expression or activity in the prostate tissue of AA men, or to unique mutations or polymorphisms of the AR. In Caucasian Americans...

  14. Mathematical Models of Androgen Resistance in Prostate Cancer Patients under Intermittent Androgen Suppression Therapy

    Directory of Open Access Journals (Sweden)

    Javier Baez

    2016-11-01

    Full Text Available Predicting the timing of a castrate resistant prostate cancer is critical to lowering medical costs and improving the quality of life of advanced prostate cancer patients. We formulate, compare and analyze two mathematical models that aim to forecast future levels of prostate-specific antigen (PSA. We accomplish these tasks by employing clinical data of locally advanced prostate cancer patients undergoing androgen deprivation therapy (ADT. While these models are simplifications of a previously published model, they fit data with similar accuracy and improve forecasting results. Both models describe the progression of androgen resistance. Although Model 1 is simpler than the more realistic Model 2, it can fit clinical data to a greater precision. However, we found that Model 2 can forecast future PSA levels more accurately. These findings suggest that including more realistic mechanisms of androgen dynamics in a two population model may help androgen resistance timing prediction.

  15. Stromal Androgen Receptor Roles in the Development of Normal Prostate, Benign Prostate Hyperplasia, and Prostate Cancer

    Science.gov (United States)

    Wen, Simeng; Chang, Hong-Chiang; Tian, Jing; Shang, Zhiqun; Niu, Yuanjie; Chang, Chawnshang

    2016-01-01

    The prostate is an androgen-sensitive organ that needs proper androgen/androgen receptor (AR) signals for normal development. The progression of prostate diseases, including benign prostate hyperplasia (BPH) and prostate cancer (PCa), also needs proper androgen/AR signals. Tissue recombination studies report that stromal, but not epithelial, AR plays more critical roles via the mesenchymal-epithelial interactions to influence the early process of prostate development. However, in BPH and PCa, much more attention has been focused on epithelial AR roles. However, accumulating evidence indicates that stromal AR is also irreplaceable and plays critical roles in prostate disease progression. Herein, we summarize the roles of stromal AR in the development of normal prostate, BPH, and PCa, with evidence from the recent results of in vitro cell line studies, tissue recombination experiments, and AR knockout animal models. Current evidence suggests that stromal AR may play positive roles to promote BPH and PCa progression, and targeting stromal AR selectively with AR degradation enhancer, ASC-J9, may allow development of better therapies with fewer adverse effects to battle BPH and PCa. PMID:25432062

  16. Androgen Depletion Induces Senescence in Prostate Cancer Cells through Down-regulation of Skp2

    Directory of Open Access Journals (Sweden)

    Zuzana Pernicová

    2011-06-01

    Full Text Available Although the induction of senescence in cancer cells is a potent mechanism of tumor suppression, senescent cells remain metabolically active and may secrete a broad spectrum of factors that promote tumorigenicity in neighboring malignant cells. Here we show that androgen deprivation therapy (ADT, a widely used treatment for advanced prostate cancer, induces a senescence-associated secretory phenotype in prostate cancer epithelial cells, indicated by increases in senescence-associated β-galactosidase activity, heterochromatin protein 1β foci, and expression of cathepsin B and insulin-like growth factor binding protein 3. Interestingly, ADT also induced high levels of vimentin expression in prostate cancer cell lines in vitro and in human prostate tumors in vivo. The induction of the senescence-associated secretory phenotype by androgen depletion was mediated, at least in part, by down-regulation of S-phase kinase-associated protein 2, whereas the neuroendocrine differentiation of prostate cancer cells was under separate control. These data demonstrate a previously unrecognized link between inhibition of androgen receptor signaling, down-regulation of S-phase kinase-associated protein 2, and the appearance of secretory, tumor-promoting senescent cells in prostate tumors. We propose that ADT may contribute to the development of androgen-independent prostate cancer through modulation of the tissue microenvironment by senescent cells.

  17. Lxrα regulates the androgen response in prostate epithelium.

    Science.gov (United States)

    Viennois, Emilie; Esposito, Teresa; Dufour, Julie; Pommier, Aurélien; Fabre, Stephane; Kemeny, Jean-Louis; Guy, Laurent; Morel, Laurent; Lobaccaro, Jean-Marc; Baron, Silvère

    2012-07-01

    Benign prostatic hyperplasia is a nonmalignant enlargement of the prostate that commonly occurs in older men. We show that liver X receptor (Lxr)-α knockout mice (lxrα(-/-)) develop ventral prostate hypertrophy, correlating with an overaccumulation of secreted proteins in prostatic ducts and an alteration of vesicular trafficking in epithelial cells. In the fluid of the lxrα(-/-) prostates, spermine binding protein is highly accumulated and shows a 3000-fold increase of its mRNA. This overexpression is mediated by androgen hypersensitivity in lxrα(-/-) mice, restricted to the ventral prostate. Generation of chimeric recombinant prostates demonstrates that Lxrα is involved in the establishment of the epithelial-mesenchymal interactions in the mouse prostate. Altogether these results point out the crucial role of Lxrα in the homeostasis of the ventral prostate and suggest lxrα(-/-) mice may be a good model to investigate the molecular mechanisms of benign prostatic hyperplasia.

  18. Nadir prostate-specific antigen (PSA) level and time to PSA nadir following primary androgen deprivation therapy as independent prognostic factors in a Japanese large-scale prospective cohort study (J-CaP).

    Science.gov (United States)

    Kitagawa, Yasuhide; Ueno, Satoru; Izumi, Kouji; Mizokami, Atsushi; Hinotsu, Shiro; Akaza, Hideyuki; Namiki, Mikio

    2014-04-01

    The aim of this study was to investigate whether nadir prostate-specific antigen (PSA) level and time to PSA nadir (TTN) are independent prognostic factors equivalent to the pretreatment factors in the data of the Japan Study Group of Prostate Cancer registry, which is a large, multicenter, population-based database of patients undergoing primary androgen deprivation therapy (PADT). A total of 10,958 patients treated with PADT were enrolled into the present study. Univariate and multivariate Cox proportional hazards regression analysis and Kaplan-Meier analysis were used to evaluate the associations of PSA nadir level and TTN with progression-free survival (PFS) and overall survival (OS), adjusting for the pretreatment factors adopted in the Japan Cancer of the Prostate Risk Assessment (J-CAPRA) score. Of the 10,958 patients, 3,451 (31.5%) had lymph node and/or distant metastases. The median PSA level was 27.0 ng/ml before treatment, and the nadir PSA level in 6,983 patients (63.7%) reached below 0.2 ng/ml. Disease progression occurred in 4,736 cases, and 2,163 patients died during a mean follow-up period of 3.86 years. Nadir PSA level and TTN were independent prognostic factors, similar to the pretreatment factors adopted in the J-CAPRA score. The probabilities of PFS and OS showed significant differences among the groups categorized by the combination of nadir PSA level and TTN in all J-CAPRA risk stratifications. The present study demonstrated that nadir PSA level and TTN are strong predictors in patients undergoing PADT in a large-scale prospective cohort study.

  19. Sarcosine induces increase in HER2/neu expression in androgen-dependent prostate cancer cells

    DEFF Research Database (Denmark)

    Dahl, Malin; Bouchelouche, Pierre; Kramer-Marek, Gabriela

    2011-01-01

    Increasing evidence suggests that Human epidermal growth factor receptor 2 (HER2/neu) is involved in progression of prostate cancer. Recently, sarcosine was reported to be highly increased during prostate cancer progression, and exogenous sarcosine induces an invasive phenotype in benign prostate...... that sarcosine is involved in the regulation of the oncoprotein HER2/neu. Thus, sarcosine may induce prostate cancer progression by increased HER2/neu expression. However, detailed information on cellular mechanisms remains to be elucidated.......Increasing evidence suggests that Human epidermal growth factor receptor 2 (HER2/neu) is involved in progression of prostate cancer. Recently, sarcosine was reported to be highly increased during prostate cancer progression, and exogenous sarcosine induces an invasive phenotype in benign prostate...... epithelial cells. The aim of this work was to investigate the effect of sarcosine on HER2/neu expression in prostate cancer cell lines LNCaP (androgen dependent), PC-3 and DU145 (both androgen independent). Relative amounts of HER2/neu and androgen receptor (AR) transcripts were determined using RT...

  20. Androgen receptor and immune inflammation in benign prostatic hyperplasia and prostate cancer

    Science.gov (United States)

    Izumi, Kouji; Li, Lei; Chang, Chawnshang

    2014-01-01

    Both benign prostatic hyperplasia (BPH) and prostate cancer (PCa) are frequent diseases in middle-aged to elderly men worldwide. While both diseases are linked to abnormal growth of the prostate, the epidemiological and pathological features of these two prostate diseases are different. BPH nodules typically arise from the transitional zone, and, in contrast, PCa arises from the peripheral zone. Androgen deprivation therapy alone may not be sufficient to cure these two prostatic diseases due to its undesirable side effects. The alteration of androgen receptor-mediated inflammatory signals from infiltrating immune cells and prostate stromal/epithelial cells may play key roles in those unwanted events. Herein, this review will focus on the roles of androgen/androgen receptor signals in the inflammation-induced progression of BPH and PCa. PMID:26594314

  1. Stilbenes inhibit androgen receptor expression in 22Rv1 castrate-resistant prostate cancer cells

    Science.gov (United States)

    Androgen receptor (AR) signaling plays an important role in the development and progression of prostate cancer (PCa). Importantly, AR continues to be expressed in advanced stages of castrate-resistant PCa (CRPC), where it can have ligand- independent activity. Identification of naturally occurring s...

  2. Androgen regulated genes in human prostate xenografts in mice: relation to BPH and prostate cancer.

    Directory of Open Access Journals (Sweden)

    Harold D Love

    2009-12-01

    Full Text Available Benign prostatic hyperplasia (BPH and prostate carcinoma (CaP are linked to aging and the presence of androgens, suggesting that androgen regulated genes play a major role in these common diseases. Androgen regulation of prostate growth and development depends on the presence of intact epithelial-stromal interactions. Further, the prostatic stroma is implicated in BPH. This suggests that epithelial cell lines are inadequate to identify androgen regulated genes that could contribute to BPH and CaP and which could serve as potential clinical biomarkers. In this study, we used a human prostate xenograft model to define a profile of genes regulated in vivo by androgens, with an emphasis on identifying candidate biomarkers. Benign transition zone (TZ human prostate tissue from radical prostatectomies was grafted to the sub-renal capsule site of intact or castrated male immunodeficient mice, followed by the removal or addition of androgens, respectively. Microarray analysis of RNA from these tissues was used to identify genes that were; 1 highly expressed in prostate, 2 had significant expression changes in response to androgens, and, 3 encode extracellular proteins. A total of 95 genes meeting these criteria were selected for analysis and validation of expression in patient prostate tissues using quantitative real-time PCR. Expression levels of these genes were measured in pooled RNAs from human prostate tissues with varying severity of BPH pathologic changes and CaP of varying Gleason score. A number of androgen regulated genes were identified. Additionally, a subset of these genes were over-expressed in RNA from clinical BPH tissues, and the levels of many were found to correlate with disease status. Our results demonstrate the feasibility, and some of the problems, of using a mouse xenograft model to characterize the androgen regulated expression profiles of intact human prostate tissues.

  3. Quantitative PET Imaging with Novel HER3-Targeted Peptides Selected by Phage Display to Predict Androgen-Independent Prostate Cancer Progression

    Science.gov (United States)

    2017-12-01

    demonstrated high levels of HER3 in the prostate cancer and not in the breast cancer, consistent with PET imaging (Figure 4B-C). In fact , when the PET...feedback on my research with established prostate cancer specific and imaging specific scientists in my field. I have accomplished this through...research on imaging HER3 in prostate cancer by molecular imaging scientists . Impact on Technology Transfer The technology developed by this grant has led

  4. The Relationship between Androgenic Alopecia and Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Ghasem Rahmatpour Rokni

    2016-07-01

    Full Text Available Prostate cancer (PC and Androgenic Alopecia (AGA i are both common diseases in elder men. It seems that androgen plays a crucial role in the growth and development of prostate cancer. Therefore, the current study intended to investigate the relationship between androgenic alopecia and prostate cancer. The present study is a case-control study conducted on 75 patients with prostate cancer (case group referring to Imam Khomeini Hospital in Sari, Iran. The case group was compared with the control group (75 healthy individuals. The intended questionnaire of the study included information such as the age, sex, duration of disease, stage of disease, level of PSA, time diagnosis and time of interview for all the participants. The results of interview and clinical examination along with the patient’s information all were filled in the questionnaire and were statistically analyzed by SPSS after data collection. The mean age of PC group and healthy group was respectively 69.08 ± 8.97 and 68 .45 ± 10.16 years. The average level of PSA was 10.86 ± 11.7 and 2.66 ± 2.7 ng/ml in PC and healthy group in turn. The average duration of cancer was 12.63 ± 9.19 months in PC group. Furthermore, about 6.7% of cancer patients were in stage I, 48% were stage II, 29.3% were in stage III and 16% were in stage IV of prostate cancer. Besides, the number of cancer patients who had both frontal and vertex alopecia (baldness altogether exceeded healthy individuals (P=0.002. According to the results of the present study, there was a significant relationship between prostate cancer and androgenic alopecia which might have been caused by the effect of androgens on both diseases. Consequently, androgenic alopecia can be considered as one of the risk factors associated with prostate cancer.

  5. Identification of novel androgen receptor target genes in prostate cancer

    Directory of Open Access Journals (Sweden)

    Gerald William L

    2007-06-01

    Full Text Available Abstract Background The androgen receptor (AR plays critical roles in both androgen-dependent and castrate-resistant prostate cancer (PCa. However, little is known about AR target genes that mediate the receptor's roles in disease progression. Results Using Chromatin Immunoprecipitation (ChIP Display, we discovered 19 novel loci occupied by the AR in castrate resistant C4-2B PCa cells. Only four of the 19 AR-occupied regions were within 10-kb 5'-flanking regulatory sequences. Three were located up to 4-kb 3' of the nearest gene, eight were intragenic and four were in gene deserts. Whereas the AR occupied the same loci in C4-2B (castrate resistant and LNCaP (androgen-dependent PCa cells, differences between the two cell lines were observed in the response of nearby genes to androgens. Among the genes strongly stimulated by DHT in C4-2B cells – D-dopachrome tautomerase (DDT, Protein kinase C delta (PRKCD, Glutathione S- transferase theta 2 (GSTT2, Transient receptor potential cation channel subfamily V member 3 (TRPV3, and Pyrroline-5-carboxylate reductase 1 (PYCR1 – most were less strongly or hardly stimulated in LNCaP cells. Another AR target gene, ornithine aminotransferase (OAT, was AR-stimulated in a ligand-independent manner, since it was repressed by AR siRNA knockdown, but not stimulated by DHT. We also present evidence for in vivo AR-mediated regulation of several genes identified by ChIP Display. For example, PRKCD and PYCR1, which may contribute to PCa cell growth and survival, are expressed in PCa biopsies from primary tumors before and after ablation and in metastatic lesions in a manner consistent with AR-mediated stimulation. Conclusion AR genomic occupancy is similar between LNCaP and C4-2B cells and is not biased towards 5' gene flanking sequences. The AR transcriptionally regulates less than half the genes nearby AR-occupied regions, usually but not always, in a ligand-dependent manner. Most are stimulated and a few are

  6. Andrographolide Targets Androgen Receptor Pathway in Castration-Resistant Prostate Cancer

    OpenAIRE

    Liu, Chengfei; Nadiminty, Nagalakshmi; Tummala, Ramakumar; Chun, Jae Yeon; Lou, Wei; Zhu, Yezi; Sun, Meng; Evans, Christopher P.; Zhou, Qinghua; Gao, Allen C.

    2011-01-01

    Androgen receptor (AR) signaling not only plays a pivotal role in the development of androgen-dependent prostate cancer but is also important in the growth and survival of castration-resistant prostate cancer (CRPC). The first line of treatment of androgen-dependent prostate cancer is the use of androgen deprivation therapy. However, most patients will eventually relapse due to development of CRPC. Thus, development of a strategy to target AR for treatment of CRPC is urgently needed. The auth...

  7. Mithramycin A induces apoptosis by regulating the mTOR/Mcl-1/tBid pathway in androgen-independent prostate cancer cells

    Science.gov (United States)

    Choi, Eun-Sun; Chung, Taeho; Kim, Jun-Sung; Lee, Hakmo; Kwon, Ki Han; Cho, Nam-Pyo; Cho, Sung-Dae

    2013-01-01

    Mithramycin A (Mith) is an aureolic acid-type polyketide produced by various soil bacteria of the genus Streptomyces. Mith inhibits myeloid cell leukemia-1 (Mcl-1) to induce apoptosis in prostate cancer, but the molecular mechanism underlying this process has not been fully elucidated. The aim of this study was therefore to investigate the detailed molecular mechanism related to Mith-induced apoptosis in prostate cancer cells. Mith decreased the phosphorylation of mammalian target of rapamycin (mTOR) in both cell lines overexpressing phospho-mTOR compared to RWPE-1 human normal prostate epithelial cells. Mith significantly induced truncated Bid (tBid) and siRNA-mediated knock-down of Mcl-1 increased tBid protein levels. Moreover, Mith also inhibited the phosphorylation of mTOR on serine 2448 and Mcl-1, and increased tBid protein in prostate tumors in athymic nude mice bearing DU145 cells as xenografts. Thus, Mith acts as an effective tumor growth inhibitor in prostate cancer cells through the mTOR/Mcl-1/tBid signaling pathway. PMID:24062605

  8. Androgen receptor overexpression in prostate cancer in type 2 diabetes

    Directory of Open Access Journals (Sweden)

    Stefan Zoltán Lutz

    2018-02-01

    Conclusions: We report elevated androgen receptor signaling and activity presumably due to altered insulin/IGF-1 receptors and decreased levels of protective estrogen receptor ligands in prostate cancer in men with diabetes. Our results reveal new insights why these patients have a worse prognosis. These findings provide the basis for future clinical trials to investigate treatment response in patients with prostate cancer and diabetes.

  9. PTTG1, A novel androgen responsive gene is required for androgen-induced prostate cancer cell growth and invasion

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Zheng [Department of Urology, First Hospital, Peking University & Institute of Urology, Peking University, Beijing 100034 (China); Jin, Bo [Department of Clinical Laboratory, Peking University First Hospital, Beijing 100034 (China); Jin, Yaqiong [Biobank for Clinical Data and Samples in Pediatric, Beijing Pediatric Research Institute, Beijing Children' s Hospital, Capital Medical University, Beijing 100045 (China); Huang, Shengquan; Niu, Xiaohua [Department of Urology, First Hospital, Peking University & Institute of Urology, Peking University, Beijing 100034 (China); Mao, Zebin [The Department of Biochemistry and Molecular Biology, Health Science Center, Peking University, 38 Xueyuan Road, Beijing 100191 (China); Xin, Dianqi, E-mail: xin-dianqi@163.com [Department of Urology, First Hospital, Peking University & Institute of Urology, Peking University, Beijing 100034 (China)

    2017-01-01

    Androgens (AR) play an important role in initiation and progression of prostate cancer. It has been shown that AR exert their effects mainly through the androgen-activated AR which binds to androgen response elements (AREs) in the regulatory regions of target genes to regulate the transcription of androgen-responsive genes, thus, identification of AR downstream target gene is critical to understand androgen function in prostate cancer. In this study, our results showed that androgen treatment of LNCaP cells induced PTTG1 expression, which was blocked by the androgen receptor antagonist, Casodex. Bioinformatics analysis and experiments using PTTG1 promoter deletion mutants showed that the PTTG1 promoter contains a putative androgen response element (ARE), which localizes in the −851 to −836 region of the promoter. Androgen activated androgen receptor (AR) binding to this ARE was confirmed by Chromatin immunoprecipitation (ChIP) assay. Furthermore, Knockdown of PTTG1 expression using short hairpin RNA significantly reduced androgen-induced LNCaP cell growth and invasion. In addition, we showed PTTG1 is highly expressed in metastasis prostate cancer tissue. These results suggest that PTTG1 is a novel downstream target gene of androgen receptor and take part in prostate cancer proliferation and metastasis. - Highlights: • Androgen treatment of LNCaP cells induced PTTG1 expression. • Knockdown of PTTG1 expression significantly reduced androgen-induced LNCaP cell growth and invasion. • PTTG1 is highly expressed in metastasis prostate cancer tissue. • PTTG1 is a novel downstream target gene of androgen receptor.

  10. Continuous vs. intermittent androgen deprivation therapy for metastatic prostate cancer

    NARCIS (Netherlands)

    Langenhuijsen, J.F.; Badhauser, D.; Schaaf, B.; Kiemeney, L.A.L.M.; Witjes, J.A.; Mulders, P.F.A.

    2013-01-01

    OBJECTIVES: To analyze the predictive value of PSA for progression and the role of testosterone for quality of life (QOL) in patients with androgen deprivation therapy (ADT) for metastatic prostate cancer. MATERIALS AND METHODS: PSA and testosterone data were used from a phase III trial randomizing

  11. Association of androgen metabolism gene polymorphisms with prostate cancer risk and androgen concentrations: Results from the Prostate Cancer Prevention Trial.

    Science.gov (United States)

    Price, Douglas K; Chau, Cindy H; Till, Cathee; Goodman, Phyllis J; Leach, Robin J; Johnson-Pais, Teresa L; Hsing, Ann W; Hoque, Ashraful; Parnes, Howard L; Schenk, Jeannette M; Tangen, Catherine M; Thompson, Ian M; Reichardt, Juergen K V; Figg, William D

    2016-08-01

    Prostate cancer is highly influenced by androgens and genes. The authors investigated whether genetic polymorphisms along the androgen biosynthesis and metabolism pathways are associated with androgen concentrations or with the risk of prostate cancer or high-grade disease from finasteride treatment. A nested case-control study from the Prostate Cancer Prevention Trial using data from men who had biopsy-proven prostate cancer (cases) and a group of biopsy-negative, frequency-matched controls was conducted to investigate the association of 51 single nucleotide polymorphisms (SNPs) in 12 genes of the androgen pathway with overall (total), low-grade, and high-grade prostate cancer incidence and serum hormone concentrations. There were significant associations of genetic polymorphisms in steroid 5α-reductase 1 (SRD5A1) (reference SNPs: rs3736316, rs3822430, rs1560149, rs248797, and rs472402) and SRD5A2 (rs2300700) with the risk of high-grade prostate cancer in the placebo arm of the Prostate Cancer Prevention Trial; 2 SNPs were significantly associated with an increased risk (SRD5A1 rs472402 [odds ratio, 1.70; 95% confidence interval, 1.05-2.75; Ptrend = .03] and SRD5A2 rs2300700 [odds ratio, 1.94; 95% confidence interval, 1.19-3.18; Ptrend = .01]). Eleven SNPs in SRD5A1, SRD5A2, cytochrome P450 family 1, subfamily B, polypeptide 1 (CYP1B1), and CYP3A4 were associated with modifying the mean concentrations of serum androgen and sex hormone-binding globulin; and 2 SNPs (SRD5A1 rs824811 and CYP1B1 rs10012; Ptrend cancer risk. Germline genetic variations of androgen-related pathway genes are associated with serum androgen concentrations and the risk of prostate cancer. Further studies to examine the functional consequence of novel causal variants are warranted. Cancer 2016;122:2332-2340. © 2016 American Cancer Society. © 2016 American Cancer Society.

  12. Myeloid cell leukemia-1 is a key molecular target for mithramycin A-induced apoptosis in androgen-independent prostate cancer cells and a tumor xenograft animal model.

    Science.gov (United States)

    Choi, Eun-Sun; Jung, Ji-Youn; Lee, Jin-Seok; Park, Jong-Hwan; Cho, Nam-Pyo; Cho, Sung-Dae

    2013-01-01

    Mithramycin A (Mith) is a natural polyketide that has been used in multiple areas of research including apoptosis of various cancer cells. Here, we examined the critical role of Mith in apoptosis and its molecular mechanism in DU145 and PC3 prostate cancer cells and tumor xenografts. Mith decreased cell growth and induced apoptosis in DU145 and PC-3 cells. Myeloid cell leukemia-1 (Mcl-1) was over-expressed in both cell lines compared to RWPE1 cells. Mith inhibited Mcl-1 protein expression in both cells, but only altered Mcl-1 mRNA levels in PC-3 cells. We also found that Mith reduced Mcl-1 protein levels through both proteasome-dependent protein degradation and the inhibition of protein synthesis in DU145 cells. Studies using siRNA confirmed that the knockdown of Mcl-1 induced apoptosis. Mith significantly suppressed TPA-induced neoplastic cell transformation through the down-regulation of the Mcl-1 protein in JB6 cells, and suppressed the transforming activity of both cell types. Mith also inhibited tumor growth and Mcl-1 levels, in addition to inducing apoptosis, in athymic nude mice bearing DU145 cell xenografts without affecting five normal organs. Therefore, Mith inhibits cell growth and induces apoptosis by suppressing Mcl-1 in both prostate cancer cells and xenograft tumors, and thus is a potent anticancer drug candidate for prostate cancer. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  13. Nutritional Effect on Androgen-Response Gene Expression and Prostate Tumor Growth

    National Research Council Canada - National Science Library

    Wang, Zhou

    2001-01-01

    .... The dietary influence on ventral prostate weight does not seem to involve androgen action axis because dietary components did not influence the expression of several androgen-response genes, serum testosterone...

  14. Concept and viability of androgen annihilation for advanced prostate cancer.

    Science.gov (United States)

    Mohler, James L

    2014-09-01

    There remains no standard of care for patients with a rising prostate-specific antigen level after radical prostatectomy or radiotherapy but who have no radiographic metastases, even though this is the second largest group of patients with prostate cancer (CaP) in the United States. Androgen deprivation therapy (ADT) may cure some men with advanced CaP based on single-institution series and a randomized clinical trial of immediate versus delayed ADT for men found to have pelvic lymph node metastasis at the time of radical prostatectomy. ADT may be more effective when initiated for minimal disease burden, which can be detected using PSA after radical prostatectomy or radiotherapy, and if more complete disruption of the androgen axis using newer agents decreases the chance that androgen-sensitive cells survive to adapt to a low-androgen environment. Androgens may be "annihilated" simultaneously using a luteinizing hormone-releasing hormone antagonist or agonist to inhibit testicular production of testosterone, a P45017A1 (CYP17A1) inhibitor to diminish metabolism of testosterone via the adrenal pathway and dihydrotestosterone (DHT) via the backdoor pathway, a 5α-reductase (SRD5A) inhibitor to diminish testosterone reduction to DHT and backdoor metabolism of progesterone substrates to DHT, and a newer antiandrogen to compete better with DHT for the androgen receptor ligand-binding domain. Early initiation of androgen annihilation for induction as part of planned intermittent ADT should be safe, may reduce tumor burden below a threshold that allows eradication by the immune system, and may cure many men who have failed definitive local therapy. © 2014 American Cancer Society.

  15. Multivalent Peptidomimetic Conjugates as Inhibitors of Androgen Receptor Function in Therapy-Resistant Prostate Cancer

    Science.gov (United States)

    2017-10-01

    hormones that play a critical role in stimulating prostate cancer growth . Androgens activate a protein called the androgen receptor (AR), which...variants, and evaluating if they block androgen-dependent prostate cancer cell growth . To understand how these molecule blocks AR function , we will...regulates genes involved in cell growth . Although powerful anti-androgen drugs can be administered to block AR action and have been used successfully to

  16. Combined androgen blockade in the treatment of advanced prostate cancer--an overview. The Scandinavian Prostatic Cancer Group

    DEFF Research Database (Denmark)

    Iversen, P

    1997-01-01

    The value of combined androgen blockade in the treatment of patients with advanced prostate cancer is still controversial. In this review by the Scandinavian Prostatic Cancer Group, the literature addressing the concept and its clinical use is critically reviewed.......The value of combined androgen blockade in the treatment of patients with advanced prostate cancer is still controversial. In this review by the Scandinavian Prostatic Cancer Group, the literature addressing the concept and its clinical use is critically reviewed....

  17. Sarcosine induces increase in HER2/neu expression in androgen-dependent prostate cancer cells

    DEFF Research Database (Denmark)

    Dahl, Malin; Bouchelouche, Pierre; Kramer-Marek, Gabriela

    2011-01-01

    -qPCR. Total expression of HER2/neu was confirmed by Western blot (WB). HER2/neu protein on the surface of living LNCaP cells was visualized by confocal microscopy using a HER2/neu-specific fluorescent probe. Exposure of LNCaP cells to 50 μM sarcosine for 24 h resulted in a 58% increase of the HER2/neu m...... epithelial cells. The aim of this work was to investigate the effect of sarcosine on HER2/neu expression in prostate cancer cell lines LNCaP (androgen dependent), PC-3 and DU145 (both androgen independent). Relative amounts of HER2/neu and androgen receptor (AR) transcripts were determined using RT...

  18. LncRNA HOTAIR Enhances the Androgen-Receptor-Mediated Transcriptional Program and Drives Castration-Resistant Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Ali Zhang

    2015-10-01

    Full Text Available Understanding the mechanisms of androgen receptor (AR activation in the milieu of low androgen is critical to effective treatment of castration-resistant prostate cancer (CRPC. Here, we report HOTAIR as an androgen-repressed lncRNA, and, as such, it is markedly upregulated following androgen deprivation therapies and in CRPC. We further demonstrate a distinct mode of lncRNA-mediated gene regulation, wherein HOTAIR binds to the AR protein to block its interaction with the E3 ubiquitin ligase MDM2, thereby preventing AR ubiquitination and protein degradation. Consequently, HOTAIR expression is sufficient to induce androgen-independent AR activation and drive the AR-mediated transcriptional program in the absence of androgen. Functionally, HOTAIR overexpression increases, whereas HOTAIR knockdown decreases, prostate cancer cell growth and invasion. Taken together, our results provide compelling evidence of lncRNAs as drivers of androgen-independent AR activity and CRPC progression, and they support the potential of lncRNAs as therapeutic targets.

  19. IκBα mediates prostate cancer cell death induced by combinatorial targeting of the androgen receptor

    International Nuclear Information System (INIS)

    Carter, Sarah Louise; Centenera, Margaret Mary; Tilley, Wayne Desmond; Selth, Luke Ashton; Butler, Lisa Maree

    2016-01-01

    Combining different clinical agents to target multiple pathways in prostate cancer cells, including androgen receptor (AR) signaling, is potentially an effective strategy to improve outcomes for men with metastatic disease. We have previously demonstrated that sub-effective concentrations of an AR antagonist, bicalutamide, and the histone deacetylase inhibitor, vorinostat, act synergistically when combined to cause death of AR-dependent prostate cancer cells. In this study, expression profiling of human prostate cancer cells treated with bicalutamide or vorinostat, alone or in combination, was employed to determine the molecular mechanisms underlying this synergistic action. Cell viability assays and quantitative real time PCR were used to validate identified candidate genes. A substantial proportion of the genes modulated by the combination of bicalutamide and vorinostat were androgen regulated. Independent pathway analysis identified further pathways and genes, most notably NFKBIA (encoding IκBα, an inhibitor of NF-κB and p53 signaling), as targets of this combinatorial treatment. Depletion of IκBα by siRNA knockdown enhanced apoptosis of prostate cancer cells, while ectopic overexpression of IκBα markedly suppressed cell death induced by the combination of bicalutamide and vorinostat. These findings implicate IκBα as a key mediator of the apoptotic action of this combinatorial AR targeting strategy and a promising new therapeutic target for prostate cancer. The online version of this article (doi:10.1186/s12885-016-2188-2) contains supplementary material, which is available to authorized users

  20. To Die or to Survive, a Fatal Question for the Destiny of Prostate Cancer Cells after Androgen Deprivation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Kai-Xin; Firus, Jessica; Prieur, Brenda [The Vancouver Prostate Centre, 2660 Oak St., Vancouver, BC V6H 3Z6 (Canada); Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6 (Canada); Jia, William [Department of Surgery and Brain Research Centre, University of British Columbia, Vancouver, BC V6H 3Z6 (Canada); Rennie, Paul S., E-mail: prennie@interchange.ubc.ca [The Vancouver Prostate Centre, 2660 Oak St., Vancouver, BC V6H 3Z6 (Canada); Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6 (Canada)

    2011-03-24

    Prostate cancer is the most frequently diagnosed non-skin cancer in adult males in North America and is the second leading cause of cancer-related mortality. For locally advanced or metastatic disease, androgen deprivation, through medical or surgical castration, is the primary treatment to induce prostate cancer cell death and extend patient survival. However, the vast majority of cancers progress to a castration-resistant/androgen-independent state where the cell death processes are no longer active. This review describes the main cell death processes, apoptosis, autophagy, necrosis and necroptosis, which may be activated in prostate cancers after androgen deprivation therapy as well as the molecular mechanisms through which the cancers progress to become castration resistant. In particular, the central role of persistent androgen receptor (AR)-mediated signaling and AR crosstalk with other critical cell signaling pathways, including (i) the PI3K/Akt pathway, (ii) receptor tyrosine kinases, (iii) the p38 MAPK pathway, and (iv) the Wnt/β-catenin pathway, as well as reactivation of AR by de novo synthesized androgen are discussed in this context. Understanding the molecular changes that subvert normal cell death mechanisms and thereby compromise the survival of prostate cancer patients continues to be a major challenge.

  1. Calcium regulation of androgen receptor expression in the human prostate cancer cell line LNCaP

    NARCIS (Netherlands)

    L.J. Blok (Leen); J.E. Perry; J.K. Lindzey; D.J. Tindall; Y. Gong (Yuewen)

    1995-01-01

    textabstractElevation of intracellular calcium levels in the presence of normal androgen levels has been implicated in apoptotic prostate cell death. Since the androgen receptor (AR) plays a critical role in the regulation of growth and differentiation of the prostate, it was of

  2. Neoadjuvant androgen withdrawal prior to external radiotherapy for locally advanced adenocarcinoma of the prostate

    International Nuclear Information System (INIS)

    Hara, Isao; Miyake, Hideaki

    2002-01-01

    It is unclear whether positive interactions between radiation and androgen withdrawal for patients with locally advanced prostate cancer is synergistic or additive. The present study aimed to clarify the significance of neoadjuvant androgen ablation prior to external radiotherapy in a human prostate LNCaP tumor model and in patients with locally advanced prostate cancer. Comparisons were made between the effect of castration prior to radiation on the growth of subcutaneous LNCaP tumors implanted into male nude mice and their serum prostate-specific antigen (PSA) levels, and the results of castration or radiation alone. Twenty-nine patients with histologically proven and locally advanced adenocarcinoma of the prostate were treated with luteinizing hormone-releasing hormone analog at least 3 months before, during, and after external radiation therapy with a total dose of 70 Gy. The toxicity and response to this therapy were evaluated. Treatment combining castration and radiation resulted in synergistic inhibition of LNCaP tumor growth and a significant delay in the emergence of androgen-independent recurrence as opposed to either treatment alone. The external radiotherapy was completed in 28 patients (96.6%), resulting in a reduction of serum PSA levels in all 28 patients to below 1.0 ng/mL. All patients were alive after a mean follow-up period of 34 months (range 11-53) with a 3-year PSA relapse-free survival rate of 83.7%. Among several factors examined, only the Gleason score was significantly associated with PSA relapse-free survival in univariate analysis, but not in multivariate analysis. Thirteen of 28 patients (46%) and 7 of 28 (25%) also showed at least one form of gastrointestinal or genitourinary toxicity, respectively. Of these patients, 8 with gastrointestinal toxicities, and 1 with genitourinary toxicity, experienced acute complications higher than grade 3. The experimental findings objectively suggested the use of neoadjuvant androgen withdrawal prior

  3. "Topological significance" analysis of gene expression and proteomic profiles from prostate cancer cells reveals key mechanisms of androgen response.

    Directory of Open Access Journals (Sweden)

    Adaikkalam Vellaichamy

    2010-06-01

    Full Text Available The problem of prostate cancer progression to androgen independence has been extensively studied. Several studies systematically analyzed gene expression profiles in the context of biological networks and pathways, uncovering novel aspects of prostate cancer. Despite significant research efforts, the mechanisms underlying tumor progression are poorly understood. We applied a novel approach to reconstruct system-wide molecular events following stimulation of LNCaP prostate cancer cells with synthetic androgen and to identify potential mechanisms of androgen-independent progression of prostate cancer.We have performed concurrent measurements of gene expression and protein levels following the treatment using microarrays and iTRAQ proteomics. Sets of up-regulated genes and proteins were analyzed using our novel concept of "topological significance". This method combines high-throughput molecular data with the global network of protein interactions to identify nodes which occupy significant network positions with respect to differentially expressed genes or proteins. Our analysis identified the network of growth factor regulation of cell cycle as the main response module for androgen treatment in LNCap cells. We show that the majority of signaling nodes in this network occupy significant positions with respect to the observed gene expression and proteomic profiles elicited by androgen stimulus. Our results further indicate that growth factor signaling probably represents a "second phase" response, not directly dependent on the initial androgen stimulus.We conclude that in prostate cancer cells the proliferative signals are likely to be transmitted from multiple growth factor receptors by a multitude of signaling pathways converging on several key regulators of cell proliferation such as c-Myc, Cyclin D and CREB1. Moreover, these pathways are not isolated but constitute an interconnected network module containing many alternative routes from inputs

  4. Role of ART-27, a Novel Androgen Receptor Coactivator, in Normal Prostate and Prostate Cancer

    Science.gov (United States)

    2005-04-01

    07$15.00/0 Printed m U 8 .A. Molecular Endocrino logy 21 (12):2864- 2876 Copyright C’l 2007 by The Endocrine Society d ol: 10.121G/ me.2007-0094...mutations identified in prostate cancer and androgen insensitivity syndrome display aberrant ART -27 coacti- vator function. Mol Endocrino l 19

  5. Origin of Androgen-Insensitive Poorly Differentiated Tumors in the Transgenic Adenocarcinoma of Mouse Prostate Model

    Directory of Open Access Journals (Sweden)

    Wendy J. Huss

    2007-11-01

    Full Text Available Following castration, the transgenic adenocarcinoma of mouse prostate (TRAMP model demonstrates rapid development of SV40-Tag-driven poorly differentiated tumors that express neuroendocrine cell markers. The cell population dynamics within the prostates of castrated TRAMP mice were characterized by analyzing the incorporation of 5-bromodeoxyuridine (BrdUrd and the expression of SV40-Tag, synaptophysin, and androgen receptor (AR. Fourteen days postcastration, the remaining epithelial cells and adenocarcinoma cells were nonproliferative and lacked detectable SV40-Tag or synaptophysin expression. In contrast, morphologically distinct intraglandular foci were identified which expressed SV40-Tag, synaptophysin, and Ki67, but that lacked AR expression. These proliferative SV40-Tag and synaptophysin-expressing intraglandular foci were associated with the rare BrdUrd-retaining cells. These foci expanded rapidly in the postcastration prostate environment, in contrast to the AR- and SV40-Tag-expressing adenocarcinoma cells that lost SV40-Tag expression and underwent apoptosis after castration. Intraglandular foci of synaptophysin-expressing cells were also observed in the prostates of intact TRAMP mice at a comparable frequency; however, they did not progress to rapidly expanding tumors until much later in the life of the mice. This suggests that the foci of neuroendocrine-like cells that express SV40-Tag and synaptophysin, but lack AR, arise independent of androgen-deprivation and represent the source of the poorly differentiated tumors that are the lethal phenotype in the TRAMP model.

  6. Differentially expressed androgen-regulated genes in androgen-sensitive tissues reveal potential biomarkers of early prostate cancer.

    Science.gov (United States)

    Altintas, Dogus Murat; Allioli, Nathalie; Decaussin, Myriam; de Bernard, Simon; Ruffion, Alain; Samarut, Jacques; Vlaeminck-Guillem, Virginie

    2013-01-01

    Several data favor androgen receptor implication in prostate cancer initiation through the induction of several gene activation programs. The aim of the study is to identify potential biomarkers for early diagnosis of prostate cancer (PCa) among androgen-regulated genes (ARG) and to evaluate comparative expression of these genes in normal prostate and normal prostate-related androgen-sensitive tissues that do not (or rarely) give rise to cancer. ARG were selected in non-neoplastic adult human prostatic epithelial RWPE-1 cells stably expressing an exogenous human androgen receptor, using RNA-microarrays and validation by qRT-PCR. Expression of 48 preselected genes was quantified in tissue samples (seminal vesicles, prostate transitional zones and prostate cancers, benign prostatic hypertrophy obtained from surgical specimens) using TaqMan® low-density arrays. The diagnostic performances of these potential biomarkers were compared to that of genes known to be associated with PCa (i.e. PCA3 and DLX1). By crossing expression studies in 26 matched PCa and normal prostate transitional zone samples, and 35 matched seminal vesicle and PCa samples, 14 genes were identified. Similarly, 9 genes were overexpressed in 15 benign prostatic hypertrophy samples, as compared to PCa samples. Overall, we selected 8 genes of interest to evaluate their diagnostic performances in comparison with that of PCA3 and DLX1. Among them, 3 genes: CRYAB, KCNMA1 and SDPR, were overexpressed in all 3 reference non-cancerous tissues. The areas under ROC curves of these genes reached those of PCA3 (0.91) and DLX1 (0.94). We identified ARG with reduced expression in PCa and with significant diagnostic values for discriminating between cancerous and non-cancerous prostatic tissues, similar that of PCA3. Given their expression pattern, they could be considered as potentially protective against prostate cancer. Moreover, they could be complementary to known genes overexpressed in PCa and included along

  7. Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer.

    OpenAIRE

    Asim, Mohammad; Tarish, Firas; Zecchini, Heather I; Sanjiv, Kumar; Gelali, Eleni; Massie, Charles Edward; Baridi, Ajoeb; Warren, Anne Y; Zhao, Wanfeng; Ogris, Christoph; McDuffus, Leigh-Anne; Mascalchi, Patrice; Shaw, Greg; Dev, Harveer; Wadhwa, Karan

    2017-01-01

    Emerging data demonstrate homologous recombination (HR) defects in castration resistant prostate cancers, rendering these tumours sensitive to PARP inhibition. Here, we demonstrate a direct requirement for the androgen receptor (AR) to maintain HR gene expression and HR activity in prostate cancer. We show that PARP-mediated repair pathways are upregulated in prostate cancer following androgen-deprivation therapy (ADT). Furthermore, upregulation of PARP activity is essential for the survival...

  8. Androgen Metabolism in Progression to Androgen-Independent Prostate Cancer

    Science.gov (United States)

    2011-06-01

    Neutrophils 1 0 0 Fatigue 22 1 1 Constitutional, other 2 0 0 INR 0 0 1 Rash/desquamation 1 0 0 Hot flashes 3 0 0 Anorexia 5 0 0 Dehydration 0 1 0 Nausea 11 4...and dutasteride (0.5 mg/d). Dose modifications for toxicity were specified. Patients were evaluated every 4 weeks, with history , physical examination...treatment at 5 weeks for pain management and 1 pa- tient stopped at 8 months for nerve root compression. Toxicity. Toxicities were reported among all patients

  9. Elevated LIM kinase 1 in nonmetastatic prostate cancer reflects its role in facilitating androgen receptor nuclear translocation.

    Science.gov (United States)

    Mardilovich, Katerina; Gabrielsen, Mads; McGarry, Lynn; Orange, Clare; Patel, Rachana; Shanks, Emma; Edwards, Joanne; Olson, Michael F

    2015-01-01

    Prostate cancer affects a large proportion of the male population, and is primarily driven by androgen receptor (AR) activity. First-line treatment typically consists of reducing AR signaling by hormone depletion, but resistance inevitably develops over time. One way to overcome this issue is to block AR function via alternative means, preferably by inhibiting protein targets that are more active in tumors than in normal tissue. By staining prostate cancer tumor sections, elevated LIM kinase 1 (LIMK1) expression and increased phosphorylation of its substrate Cofilin were found to be associated with poor outcome and reduced survival in patients with nonmetastatic prostate cancer. A LIMK-selective small molecule inhibitor (LIMKi) was used to determine whether targeted LIMK inhibition was a potential prostate cancer therapy. LIMKi reduced prostate cancer cell motility, as well as inhibiting proliferation and increasing apoptosis in androgen-dependent prostate cancer cells more effectively than in androgen-independent prostate cancer cells. LIMK inhibition blocked ligand-induced AR nuclear translocation, reduced AR protein stability and transcriptional activity, consistent with its effects on proliferation and survival acting via inhibition of AR activity. Furthermore, inhibition of LIMK activity increased αTubulin acetylation and decreased AR interactions with αTubulin, indicating that the role of LIMK in regulating microtubule dynamics contributes to AR function. These results indicate that LIMK inhibitors could be beneficial for the treatment of prostate cancer both by reducing nuclear AR translocation, leading to reduced proliferation and survival, and by inhibiting prostate cancer cell dissemination. ©2014 American Association for Cancer Research.

  10. Positive HER-2 protein expression in circulating prostate cells and micro-metastasis, resistant to androgen blockage but not diethylstilbestrol

    Directory of Open Access Journals (Sweden)

    Nigel P Murray

    2011-01-01

    Full Text Available Introduction : HER-2 expression in prostate cancer is associated with a worse prognosis and is suggested to play a role in androgen resistance. We present a study of HER-2 expression in circulating tumor cells and micrometastasis in bone marrow and the effect of androgen blockage or DES in the presence of HER-2 expressing cells. Patients and Methods : A multicenter study of men with prostate cancer, treated with surgery, radiotherapy, or observation, and with or without hormone therapy. Mononuclear cells were separated from blood and bone marrow aspirate by differential centrifugation, touch preps were made from bone marrow biopsy samples. Prostate cells were detected using anti-PSA monoclonal antibody and standard immunocytochemistry. Positive samples were processed using Herceptest® to determine HER-2 expression. After 1 year, patients were re-evaluated and the findings of HER-2 expression and PSA change compared with treatment. Results : Total 199 men participated, and 97 had a second evaluation 1 year later, frequency of HER-2 expression in circulating tumor cells and micrometastasis was 18% and 21%, respectively. There was no significant difference in HER-2 expression in the pretreatment group, after radical surgery or radiotherapy or with biochemical failure. Men with androgen blockade had a significantly higher expression of HER-2 (58% (P =0.001. Of the 97 men with a second evaluation, 56 were in the observation arm, 27 androgen blockade, and 14 DES. Use of androgen blockade or DES significantly reduced serum PSA levels in comparison with observation (P =0.001. However, there was a significant increase in HER-2 expression in patients with androgen blockade (P =0.05 en comparison with observation or DES treatment. No patient with observation or DES became HER-2 positive, en comparison 4/22 patients initially HER-2 negative became HER-2 positive with androgen blockade. Conclusions : The results suggest that HER-2 positive cells are

  11. Telomerase as an Androgen Receptor-Regulated Target in Selenium Chemoprevention of Prostate Cancer

    Science.gov (United States)

    2011-04-01

    androgens through de novo steroidogenesis (41–43). Xeno - graft studies have shown that knocking down AR expres- sion by shRNA could delay the progression...AD_________________ Award Number: W81XWH-08-1-0291 TITLE: Telomerase as an Androgen Receptor...March 2011 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Telomerase as an Androgen Receptor-Regulated Target in Selenium Chemoprevention of Prostate

  12. Seminal Plasma Proteins as Androgen Receptor Coregulators Promote Prostate Cancer Growth

    Science.gov (United States)

    2014-10-01

    the presence of zinc was found to induce androgen-mediated PSA expression in AR-positive prostate cancer cells. Reportable Outcomes Ishiguro ...prostatectomy. Hum Pathol 43: 6 1991–2000, 2012. Appendix Ishiguro H, Izumi K, Zheng Y, Kashiwagi E, Kawahara T, Miyamoto H: Semenogelin I promotes...PROSTATE CANCER CELL GROWTH VIA FUNCTIONING AS AN ANDROGEN RECEPTOR COACTIVATOR AND PROTECTING AGAINST ZINC CYTOTOXICITY Hitoshi Ishiguro *, Baltimore

  13. Androgenic alopecia is not useful as an indicator of men at high risk of prostate cancer.

    NARCIS (Netherlands)

    Cremers, R.G.H.M.; Aben, K.K.H.; Vermeulen, S.; Heijer, M. den; Oort, I.M. van; Kiemeney, L.A.L.M.

    2010-01-01

    BACKGROUND: Androgens are assumed to play a central role in the pathophysiology of both prostate cancer (PC) and androgenic alopecia (AA). A correlation between the two phenotypes may be relevant for identification of men at high risk of PC. We evaluated the association between AA at different ages

  14. Biopsychosocial impact of prostate cancer and androgen-deprivation therapy.

    Science.gov (United States)

    Tripp, Dean A; Verreault, Phylicia; Tong, Steven; Izard, Jason; Black, Angela; Siemens, D Robert

    2017-10-01

    Prostate cancer is the most non-cutaneous malignancy in men, and androgen-deprivation therapy (ADT) is a cornerstone of management in advanced disease. The aim of this study was to evaluate the association of ADT with changes in depression and mental and physical quality of life (QoL) within a prospective patient cohort design. Patients were prospectively recruited and consented at a single academic health sciences centre in Ontario, Canada. Inclusion criteria included those men with adenocarcinoma of the prostate and either on watchful waiting or initiating ADT as palliation or as an adjuvant therapy for high-risk localized disease. All three cohorts were followed in routine care and completed psychosocial evaluations, including depression, social support, anxiety, and QoL measures. In comparison to the control cohort of patients with prostate cancer on watchful waiting, initiation of ADT over a two-year period of time was not associated with any changes in depression or mental QoL. Instead, all patients, regardless of treatment cohort, showed increased depression scores and reduced mental QoL scores over time; however, for patients receiving ADT, a significant reduction in physical QoL compared to patients who did not receive ADT was demonstrated. ADT does not appear to significantly impact depressive symptoms and mental QoL over a two-year period; however, the depressive symptoms in this limited sample of men with prostate cancer was higher than expected and monitoring for these may be advisable for those who care for such patients.

  15. Metabolic sequelae associated with androgen deprivation therapy for prostate cancer.

    Science.gov (United States)

    Faris, Jason E; Smith, Matthew R

    2010-06-01

    To summarize the metabolic alterations associated with androgen deprivation therapy (ADT) for prostate cancer and to evaluate the evidence linking ADT with an increased risk of diabetes and cardiovascular disease. ADT by either bilateral orchiectomy or treatment with gonadotropin-releasing hormone agonists causes changes in body composition, alterations in lipid profiles, and decreased insulin sensitivity. The spectrum of metabolic changes during ADT is distinct from classically described metabolic syndrome. Population-based, linked cancer registry studies have consistently reported significant associations between ADT and greater risk for diabetes mellitus. Some but not all studies have reported a link between ADT and cardiovascular disease risk. Most studies have reported no increase in cardiovascular mortality following ADT. ADT appears causally associated with diabetes mellitus. ADT is also linked to cardiovascular morbidity, although there is less evidence that this relationship is causal.

  16. P-glycoprotein increases the efflux of the androgen dihydrotestosterone and reduces androgen responsive gene activity in prostate tumor cells.

    Science.gov (United States)

    Fedoruk, Matthew N; Giménez-Bonafé, Pepita; Guns, Emma S; Mayer, Lawrence D; Nelson, Colleen C

    2004-04-01

    P-glycoprotein (P-gp) is commonly associated with multi-drug resistance (MDR) in cancer cells and the efflux of a broad spectrum of chemicals from the cell, including many chemotherapeutics and certain steroid hormones. The impact of P-gp and mechanisms involved in androgen transport and cellular accumulation within normal and malignant prostate cells remains unclear. Following incubation of LNCaP, PC-3, HeLa, and HeLa FLAG-androgen receptor (AR) cells with (3)H-dihydrotestosterone (DHT) alone and in combination with P-gp inhibitors, PSC-833 and verapamil, we examined the cellular accumulation and efflux of androgens, as well as gene transcriptional response. Our data reveal that the cellular transport and accumulation of DHT is dependent on the expression of functional AR and modulated by P-gp. P-gp over-expression by both transient transfection and aspirin treatment in LNCaP cells showed decreased intracellular DHT accumulation, further suggesting DHT efflux is P-gp regulated. Androgen responsiveness may be modulated by P-gp in prostate cancer cells. The biological consequences of increased P-gp expression are decreased androgen accumulation and a corresponding decrease in androgen-regulated transcriptional activity and PSA gene expression. Copyright 2004 Wiley-Liss, Inc.

  17. Oncolytic targeting of androgen-sensitive prostate tumor by the respiratory syncytial virus (RSV: consequences of deficient interferon-dependent antiviral defense

    Directory of Open Access Journals (Sweden)

    Hubbard Gene B

    2011-01-01

    Full Text Available Abstract Background Oncolytic virotherapy for cancer treatment utilizes viruses for selective infection and death of cancer cells without any adverse effect on normal cells. We previously reported that the human respiratory syncytial virus (RSV is a novel oncolytic virus against androgen-independent PC-3 human prostate cancer cells. The present study extends the result to androgen-dependent prostate cancer, and explores the underlying mechanism that triggers RSV-induced oncolysis of prostate cancer cells. Methods The oncolytic effect of RSV on androgen-sensitive LNCaP human prostate cancer cells and on androgen-independent RM1 murine prostate cancer cells was studied in vitro in culture and in vivo in a xenograft or allograft tumor model. In vitro, cell viability, infectivity and apoptosis were monitored by MTT assay, viral plaque assay and annexin V staining, respectively. In vivo studies involved virus administration to prostate tumors grown in immune compromised nude mice and in syngeneic immune competent C57BL/6J mice. Anti-tumorogenic oncolytic activity was monitored by measuring tumor volume, imaging bioluminescent tumors in live animals and performing histopathological analysis and TUNEL assay with tumors Results We show that RSV imposes a potent oncolytic effect on LNCaP prostate cancer cells. RSV infectivity was markedly higher in LNCaP cells compared to the non-tumorigenic RWPE-1 human prostate cells. The enhanced viral burden led to LNCaP cell apoptosis and growth inhibition of LNCaP xenograft tumors in nude mice. A functional host immune response did not interfere with RSV-induced oncolysis, since growth of xenograft tumors in syngeneic C57BL/6J mice from murine RM1 cells was inhibited upon RSV administration. LNCaP cells failed to activate the type-I interferon (IFNα/β-induced transcription factor STAT-1, which is required for antiviral gene expression, although these cells could produce IFN in response to RSV infection. The

  18. Differentially expressed androgen-regulated genes in androgen-sensitive tissues reveal potential biomarkers of early prostate cancer.

    Directory of Open Access Journals (Sweden)

    Dogus Murat Altintas

    Full Text Available BACKGROUND: Several data favor androgen receptor implication in prostate cancer initiation through the induction of several gene activation programs. The aim of the study is to identify potential biomarkers for early diagnosis of prostate cancer (PCa among androgen-regulated genes (ARG and to evaluate comparative expression of these genes in normal prostate and normal prostate-related androgen-sensitive tissues that do not (or rarely give rise to cancer. METHODS: ARG were selected in non-neoplastic adult human prostatic epithelial RWPE-1 cells stably expressing an exogenous human androgen receptor, using RNA-microarrays and validation by qRT-PCR. Expression of 48 preselected genes was quantified in tissue samples (seminal vesicles, prostate transitional zones and prostate cancers, benign prostatic hypertrophy obtained from surgical specimens using TaqMan® low-density arrays. The diagnostic performances of these potential biomarkers were compared to that of genes known to be associated with PCa (i.e. PCA3 and DLX1. RESULTS AND DISCUSSION: By crossing expression studies in 26 matched PCa and normal prostate transitional zone samples, and 35 matched seminal vesicle and PCa samples, 14 genes were identified. Similarly, 9 genes were overexpressed in 15 benign prostatic hypertrophy samples, as compared to PCa samples. Overall, we selected 8 genes of interest to evaluate their diagnostic performances in comparison with that of PCA3 and DLX1. Among them, 3 genes: CRYAB, KCNMA1 and SDPR, were overexpressed in all 3 reference non-cancerous tissues. The areas under ROC curves of these genes reached those of PCA3 (0.91 and DLX1 (0.94. CONCLUSIONS: We identified ARG with reduced expression in PCa and with significant diagnostic values for discriminating between cancerous and non-cancerous prostatic tissues, similar that of PCA3. Given their expression pattern, they could be considered as potentially protective against prostate cancer. Moreover, they could

  19. 1,4-Substituted Triazoles as Nonsteroidal Anti-Androgens for Prostate Cancer Treatment.

    Science.gov (United States)

    Ferroni, Claudia; Pepe, Antonella; Kim, Yeong Sang; Lee, Sunmin; Guerrini, Andrea; Parenti, Marco Daniele; Tesei, Anna; Zamagni, Alice; Cortesi, Michela; Zaffaroni, Nadia; De Cesare, Michelandrea; Beretta, Giovanni Luca; Trepel, Jane B; Malhotra, Sanjay V; Varchi, Greta

    2017-04-13

    Prostate cancer (PC) is the fifth leading cause of cancer death in men, and the androgen receptor (AR) represents the primary target for PC treatment, even though the disease frequently progresses toward androgen-independent forms. Most of the commercially available nonsteroidal antiandrogens show a common scaffold consisting of two aromatic rings connected by a linear or a cyclic spacer. By taking advantage of a facile, one-pot click chemistry reaction, we report herein the preparation of a small library of novel 1,4-substituted triazoles with AR antagonistic activity. Biological and theoretical evaluation demonstrated that the introduction of the triazole core in the scaffold of nonsteroidal antiandrogens allowed the development of small molecules with improved overall AR-antagonist activity. In fact, compound 14d displayed promising in vitro antitumor activity toward three different prostate cancer cell lines and was able to induce 60% tumor growth inhibition of the CW22Rv1 in vivo xenograft model. These results represent a step toward the development of novel and improved AR antagonists.

  20. Enhanced radiosensitization of enzalutamide via schedule dependent administration to androgen-sensitive prostate cancer cells.

    Science.gov (United States)

    Ghashghaei, Maryam; Paliouras, Miltiadis; Heravi, Mitra; Bekerat, Hamed; Trifiro, Mark; Niazi, Tamim M; Muanza, Thierry

    2018-01-01

    Prostate cancer (PCa) is a progressive disease and the most diagnosed cancer in men. The current standard of care for high-risk localized PCa is a combination of androgen deprivation therapy (ADT) and radiation (XRT). The majority of these patients however become resistant due to incomplete responses to ADT as a result of selective cells maintaining androgen receptor (AR) activity. Improvement can be made if increasing radiosensitivity is realized. Therefore, the aim of this study is to investigate the efficacy of the next-generation PCa drug Enzalutamide (ENZA), as a radiosensitizer in XRT therapy. Using a number of androgen-dependent (LNCaP, PC3-T877A) and androgen-independent (C4-2, 22RV1, PC3, PC3-AR V7) cell lines, the effect of ENZA as a radiosensitizer was studied alone or in combination with ADT and/or XRT. Cell viability and cell survival were assessed, along with determination of cell cycle arrest, DNA damage response and repair, apoptosis and senescence. Our results indicated that either ENZA alone (in AR positive, androgen-dependent PCa cells) or in combination with ADT (in AR positive, hormone-insensitive PCa cells) potentiates radiation response [Dose enhancement factor (DEF) of 1.75 in LNCAP and 1.35 in C4-2] stronger than ADT + XRT conditions. Additionally, ENZA sensitized androgen dependent PCa cells to XRT in a schedule-dependent manner, where concurrent administration of ENZA and radiation lead to a maximal radiosensitization when compared to either drug administration prior or after XRT. In LNCaP cells, ENZA treatment significantly prolonged the presence of XRT-induced phospho-γH2AX up to 24 h after treatment; suggesting enhanced DNA damage. It also significantly increased XRT-induced apoptosis and senescence. Our data indicates that ENZA acts as a much stronger radiosensitizer compared to ADT. We have also observed that its efficacy is schedule dependent and related to increased levels of DNA damage and a delay of DNA repair processes

  1. Duration of short-course androgen suppression therapy and the risk of death as a result of prostate cancer.

    LENUS (Irish Health Repository)

    D'Amico, Anthony V

    2011-12-10

    We evaluated whether the duration of androgen suppression therapy (AST) had an impact on the risk of prostate cancer-specific mortality (PCSM) in men with unfavorable-risk prostate cancer (PC) within established Gleason score (GS) categories.

  2. Andrographolide targets androgen receptor pathway in castration-resistant prostate cancer.

    Science.gov (United States)

    Liu, Chengfei; Nadiminty, Nagalakshmi; Tummala, Ramakumar; Chun, Jae Yeon; Lou, Wei; Zhu, Yezi; Sun, Meng; Evans, Christopher P; Zhou, Qinghua; Gao, Allen C

    2011-02-01

    Androgen receptor (AR) signaling not only plays a pivotal role in the development of androgen-dependent prostate cancer but is also important in the growth and survival of castration-resistant prostate cancer (CRPC). The first line of treatment of androgen-dependent prostate cancer is the use of androgen deprivation therapy. However, most patients will eventually relapse due to development of CRPC. Thus, development of a strategy to target AR for treatment of CRPC is urgently needed. The authors have previously identified andrographolide as an inhibitor of interleukin-6, which can suppress tumor growth of prostate cancer cells by screening compounds from the Prestwick Natural compound library. In this study, they identified that andrographolide can inhibit AR expression and prostate cancer cell growth and induce apoptosis. Andrographolide is able to down-regulate AR expression at both mRNA and protein levels, prevents its nuclear translocation, and inhibits transactivation of its target genes. Andrographolide prevents the binding of Hsp90 to AR, resulting in proteasome-mediated AR degradation. Furthermore, andrographolide inhibits castration-resistant C4-2 cell growth by reducing AR expression and activity. Thus, andrographolide can be developed as a potential therapeutic agent for prostate cancer by inhibition of androgen receptor signaling.

  3. Androgens and estrogens in benign prostatic hyperplasia: past, present and future

    Science.gov (United States)

    Nicholson, Tristan M.; Ricke, William A.

    2011-01-01

    Benign prostatic hyperplasia (BPH) and associated lower urinary tract symptoms (LUTS) are common clinical problems in urology. While the precise molecular etiology remains unclear, sex steroids have been implicated in the development and maintenance of BPH. Sufficient data exists linking androgens and androgen receptor pathways to BPH and use of androgen reducing compounds, such as 5α-reductase inhibitors which block the conversion of testosterone into dihydrotestosterone, are a component of the standard of care for men with LUTS attributed to an enlarged prostate. However, BPH is a multifactorial disease and not all men respond well to currently available treatments, suggesting factors other than androgens are involved. Testosterone, the primary circulating androgen in men, can also be metabolized via CYP19/aromatase into the potent estrogen, estradiol-17β. The prostate is an estrogen target tissue and estrogens directly and indirectly affect growth and differentiation of prostate. The precise role of endogenous and exogenous estrogens in directly affecting prostate growth and differentiation in the context of BPH is an understudied area. Estrogens and selective estrogen receptor modulators (SERMs) have been shown to promote or inhibit prostate proliferation signifying potential roles in BPH. Recent research has demonstrated that estrogen receptor signaling pathways may be important in the development and maintenance of BPH and LUTS; however, new models are needed to genetically dissect estrogen regulated molecular mechanisms involved in BPH. More work is needed to identify estrogens and associated signaling pathways in BPH in order to target BPH with dietary and therapeutic SERMs. PMID:21620560

  4. Prostate cancer characteristics associated with response to pre-receptor targeting of the androgen axis.

    Directory of Open Access Journals (Sweden)

    Elahe A Mostaghel

    Full Text Available Factors influencing differential responses of prostate tumors to androgen receptor (AR axis-directed therapeutics are poorly understood, and predictors of treatment efficacy are needed. We hypothesized that the efficacy of inhibiting DHT ligand synthesis would associate with intra-tumoral androgen ratios indicative of relative dependence on DHT-mediated growth.We characterized two androgen-sensitive prostate cancer xenograft models after androgen suppression by castration in combination with the SRD5A inhibitor, dutasteride, as well as a panel of castration resistant metastases obtained via rapid autopsy.In LuCaP35 tumors (intra-tumoral T:DHT ratio 2:1 dutasteride suppressed DHT to 0.02 ng/gm and prolonged survival vs. castration alone (337 vs.152 days, HR 2.8, p = 0.0015. In LuCaP96 tumors (T:DHT 10:1, survival was not improved despite similar DHT reduction (0.02 ng/gm. LuCaP35 demonstrated higher expression of steroid biosynthetic enzymes maintaining DHT levels (5-fold higher SRD5A1, 41 fold higher, 99-fold higher RL-HSD, p<0.0001 for both, reconstitution of intra-tumoral DHT (to ∼30% of untreated tumors, and ∼2 fold increased expression of full length AR. In contrast, LuCaP96 demonstrated higher levels of steroid catabolizing enzymes (6.9-fold higher AKR1C2, 3000-fold higher UGT2B15, p = 0.002 and p<0.0001 respectively, persistent suppression of intra-tumoral DHT, and 6-8 fold induction of full length AR and the ligand independent V7 AR splice variant. Human metastases demonstrated bio-active androgen levels and AR full length and AR splice-variant expression consistent with the range observed in xenografts.Intrinsic differences in basal steroidogenesis, as well as variable expression of full length and splice-variant AR, associate with response and resistance to pre-receptor AR ligand suppression. Expression of steroidogenic enzymes and AR isoforms may serve as potential biomarkers of sensitivity to potent AR-axis inhibition and

  5. SOCS2 mediates the cross talk between androgen and growth hormone signaling in prostate cancer

    DEFF Research Database (Denmark)

    Iglesias Gato, Diego; Chuan, Yin Choy; Wikström, Pernilla

    2014-01-01

    Anabolic signals such as androgens and the growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis play an essential role in the normal development of the prostate but also in its malignant transformation. In this study, we investigated the role of suppressor of cytokine signaling 2 (SOCS2...... with benign tissue. In contrast, however, castration-resistant bone metastases exhibit reduced levels of SOCS2 in comparison with localized or hormone naive, untreated metastatic tumors. In PCa cells, SOCS2 expression is induced by androgens through a mechanism that requires signal transducer and activator......) as mediator of the cross talk between androgens and GH signals in the prostate and its potential role as tumor suppressor in prostate cancer (PCa). We observed that SOCS2 protein levels assayed by immunohistochemistry are elevated in hormone therapy-naive localized prostatic adenocarcinoma in comparison...

  6. Ligand-specific allosteric regulation of coactivator functions of androgen receptor in prostate cancer cells

    Science.gov (United States)

    Baek, Sung Hee; Ohgi, Kenneth A.; Nelson, Charles A.; Welsbie, Derek; Chen, Charlie; Sawyers, Charles L.; Rose, David W.; Rosenfeld, Michael G.

    2006-01-01

    The androgen receptor not only mediates prostate development but also serves as a key regulator of primary prostatic cancer growth. Although initially responsive to selective androgen receptor modulators (SARMs), which cause recruitment of the nuclear receptor–corepressor (N-CoR) complex, resistance invariably occurs, perhaps in response to inflammatory signals. Here we report that dismissal of nuclear receptor–corepressor complexes by specific signals or androgen receptor overexpression results in recruitment of many of the cohorts of coactivator complexes that permits SARMs and natural ligands to function as agonists. SARM-bound androgen receptors appear to exhibit failure to recruit specific components of the coactivators generally bound by liganded nuclear receptors, including cAMP response element-binding protein (CBP)/p300 or coactivator-associated arginine methyltransferase 1 (CARM1) to the SARM-bound androgen receptor, although still causing transcriptional activation of androgen receptor target genes. SARM-bound androgen receptors use distinct LXXLL (L, leucine; X, any amino acid) helices in the p160 nuclear receptor interaction domains that may impose selective allosteric effects, providing a component of the molecular basis of differential responses to different classes of ligands by androgen receptor. PMID:16492776

  7. Maintaining intimacy for prostate cancer patients on androgen deprivation therapy.

    Science.gov (United States)

    Wassersug, Richard J

    2016-03-01

    Androgen deprivation therapy (ADT) causes erectile dysfunction and increases patients' emotionality while diminishing their sexual interest. ADT has been linked to erosion of spousal bonds; however, this is not an invariant outcome. Understanding the factors that lead to these various outcomes may help couples deal with ADT. A subset of couples report that they became closer as a result of the patients going on ADT. Recent data suggest that what helps couples most is preemptive awareness of ADT's side-effects and congruence in how patients and their partners understand and accept the psychosexual impact of ADT. Sex therapy for prostate cancer patients divides along gendered lines, with distinctly 'male' (recovery of erections) and 'female' (promoting sexual practices that are not erection dependent) approaches. Unfortunately, neither is very effective for couples when the patient is on ADT. Options beyond the standard gendered framework, such as use of an external penile prosthesis, may be worth offering to ADT patients trying to find a 'new normal' that is sexually rewarding for them. Intimacy is sharing something with someone that one shares with no one else. Exploring novel sexual practices can help couples stay intimate, even when the patient is on ADT.

  8. Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer.

    Science.gov (United States)

    Asim, Mohammad; Tarish, Firas; Zecchini, Heather I; Sanjiv, Kumar; Gelali, Eleni; Massie, Charles E; Baridi, Ajoeb; Warren, Anne Y; Zhao, Wanfeng; Ogris, Christoph; McDuffus, Leigh-Anne; Mascalchi, Patrice; Shaw, Greg; Dev, Harveer; Wadhwa, Karan; Wijnhoven, Paul; Forment, Josep V; Lyons, Scott R; Lynch, Andy G; O'Neill, Cormac; Zecchini, Vincent R; Rennie, Paul S; Baniahmad, Aria; Tavaré, Simon; Mills, Ian G; Galanty, Yaron; Crosetto, Nicola; Schultz, Niklas; Neal, David; Helleday, Thomas

    2017-08-29

    Emerging data demonstrate homologous recombination (HR) defects in castration-resistant prostate cancers, rendering these tumours sensitive to PARP inhibition. Here we demonstrate a direct requirement for the androgen receptor (AR) to maintain HR gene expression and HR activity in prostate cancer. We show that PARP-mediated repair pathways are upregulated in prostate cancer following androgen-deprivation therapy (ADT). Furthermore, upregulation of PARP activity is essential for the survival of prostate cancer cells and we demonstrate a synthetic lethality between ADT and PARP inhibition in vivo. Our data suggest that ADT can functionally impair HR prior to the development of castration resistance and that, this potentially could be exploited therapeutically using PARP inhibitors in combination with androgen-deprivation therapy upfront in advanced or high-risk prostate cancer.Tumours with homologous recombination (HR) defects become sensitive to PARPi. Here, the authors show that androgen receptor (AR) regulates HR and AR inhibition activates the PARP pathway in vivo, thus inhibition of both AR and PARP is required for effective treatment of high risk prostate cancer.

  9. Radiation therapy and androgen deprivation in the management of high risk prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Dal Pra, Alan; Cury, Fabio L.; Souhami, Luis, E-mail: luis.souhami@muhc.mcgill.c [McGill University Health Centre, Montreal, QC (Canada). Dept. of Oncology. Division of Radiation Oncology

    2011-03-15

    The combined use of radiation therapy (RT) and androgen deprivation for patients with localized high-risk prostate cancer is commonly accepted as the standard treatment among uro-oncologists. Preclinical studies have provided rationale for the use of this combination. Additionally, results of phase 3 studies using conventional doses of RT have supported the combined approach. Other phase 3 studies have also shown a benefit for using higher doses of RT; however, the role of androgen deprivation in this context is not clear. The optimal duration of the androgen deprivation, in both the neoadjuvant and adjuvant setting, is still under investigation. This article critically reviews the data on the use of RT combined with androgen deprivation for the treatment of high-risk prostate cancer with emphasis on the results of phase 3 trials. (author)

  10. Radiation therapy and androgen deprivation in the management of high risk prostate cancer

    Directory of Open Access Journals (Sweden)

    Alan Dal Pra

    2011-04-01

    Full Text Available The combined use of radiation therapy (RT and androgen deprivation for patients with localized high-risk prostate cancer is commonly accepted as the standard treatment among uro-oncologists. Preclinical studies have provided rationale for the use of this combination. Additionally, results of phase 3 studies using conventional doses of RT have supported the combined approach. Other phase 3 studies have also shown a benefit for using higher doses of RT; however, the role of androgen deprivation in this context is not clear. The optimal duration of the androgen deprivation, in both the neoadjuvant and adjuvant setting, is still under investigation. This article critically reviews the data on the use of RT combined with androgen deprivation for the treatment of high-risk prostate cancer with emphasis on the results of phase 3 trials.

  11. New Insights into the Androgen-Targeted Therapies and Epigenetic Therapies in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Abhijit M. Godbole

    2011-01-01

    Full Text Available Prostate cancer is the most common cancer in men in the United States, and it is the second leading cause of cancer-related death in American men. The androgen receptor (AR, a receptor of nuclear family and a transcription factor, is the most important target in this disease. While most efforts in the clinic are currently directed at lowering levels of androgens that activate AR, resistance to androgen deprivation eventually develops. Most prostate cancer deaths are attributable to this castration-resistant form of prostate cancer (CRPC. Recent work has shed light on the importance of epigenetic events including facilitation of AR signaling by histone-modifying enzymes, posttranslational modifications of AR such as sumoylation. Herein, we provide an overview of the structure of human AR and its key structural domains that can be used as targets to develop novel antiandrogens. We also summarize recent findings about the antiandrogens and the epigenetic factors that modulate the action of AR.

  12. Mathematical modeling of continuous and intermittent androgen suppression for the treatment of advanced prostate cancer.

    Science.gov (United States)

    Voth, Alacia M; Alford, John G; Swim, Edward W

    2017-06-01

    Prostate cancer is one of the most prevalent types of cancer among men. It is stimulated by the androgens, or male sexual hormones, which circulate in the blood and diffuse into the tissue where they stimulate the prostate tumor to grow. One of the most important treatments for advanced prostate cancer has become androgen deprivation therapy (ADT). In this paper we present three different models of ADT for prostate cancer: continuous androgen suppression (CAS), intermittent androgen suppression (IAS), and periodic androgen suppression. Currently, many patients in the U.S. receive CAS therapy of ADT, but many undergo a relapse after several years and experience adverse side effects while receiving treatment. Some clinical studies have introduced various IAS regimens in order to delay the time to relapse, and/or to reduce the economic costs and adverse side effects. We will compute and analyze parameter sensitivity analysis for CAS and IAS which may give insight to plan effective data collection in a future clinical trial. Moreover, a periodic model for IAS is used to develop an analytical formulation for relapse times which then provides information about the sensitivity of relapse to the parameters in our models.

  13. Is there a relationship between androgenic alopecia and benign prostatic hyperplasia?

    Science.gov (United States)

    Dastgheib, Ladan; Shirazi, Mehdi; Moezzi, Iman; Dehghan, Saber; Sadati, Maryam-Sadat

    2015-01-01

    Androgenic alopecia as a physiologic process and benign prostatic hyperplasia (BPH) as a pathologic process in the older population are androgen-dependent processes influenced by 5-alpha reductase enzyme which converts testosterone to dihydrotestosterone. This cross sectional study was done to evaluate the relationship between androgenic alopecia and BPH. 150 men older than 50 years old, who presented to the free prostate screening clinic, were included. They were asked about urinary symptoms. PSA level, prostate volume with sonography and alopecia grading using Hamilton-Norwood classification (grade I to VII) were evaluated. Analysis was done by SPSS statistical method. 59.6% of men had mild alopecia (grade I, II, III), 34.1% had moderate alopecia (grade IV, V) and 6.3% had severe alopecia (grade VI, VII).The mean PSA level was 1.37 ± 1.48 ng/ml. The minimum PSA level was 0.1 ng/ml, and the maximum level was 6.8 ng/ml. The mean prostate volume was 37.85 ± 21.85cc. The minimum prostate size was 10 ml, and the maximum volume was 173 ml. The mean international prostate symptom score (IPSS) was 7.6 ± 6.11 with the minimum score 0 and the maximum score 27. However, no relationship between these parameters and androgenic alopecia was detected. This study showed that there is no relationship between androgenic alopecia, PSA level, IPSS, and prostate volume. Occurrence of alopecia in younger age and a positive family history correlated with a higher grade of alopecia.

  14. A method for tissue extraction and determination of prostate concentrations of endogenous androgens by radioimmunoassay

    International Nuclear Information System (INIS)

    Albert, J.; Geller, J.; Geller, S.; Lopez, D.

    1976-01-01

    A method for simultaneously determining concentrations of major androgens in prostate has been developed. Extraction techniques used to isolate the androgens from minced tissue include homogenization with high-speed blades in Delsal's solvent mixture, adsorption to silica gel, followed by column and one thin-layer chromatography (TLC). Radioimmunoassays (RIA) of small aliquots of TLC eluates are used to quantitate picogram amounts of 5α-dihydrotestosterone (DHT) and 5α-androstanediols (Diol) and to estimate testosterone (T) and androstenedione (Ad). Contamination of blanks was reduced to RIA sensitivity limits primarily by treatment of glassware in a self-cleaning oven. The specificity of the method for each androgen was established by TLC separations of known prostate metabolites, antisera specificities, and parallelism of sample aliquots to androgen RIA standards. The overall precision, in terms of coefficients of variation, was 21% for DHT and 24% for Diol. T and Ad could not be measured with acceptable precision because their very low concentrations in prostate (<=0.5 ng/g tissue) were less than RIA sensitivity limits. Accuracy studies indicated recoveries ranging from 96% for Diol to 121% for DHT. In human benign hypertrophic prostate tissue, DHT averaged 153 ng/g soluble protein (5.8 ng/g tissue) which was 17 times higher than values obtained in human spleen and kidney; Diol in prostate showed no consistent differences from values noted in kidney or spleen

  15. ErbB-2 signaling plays a critical role in regulating androgen-sensitive and castration-resistant androgen receptor-positive prostate cancer cells.

    Science.gov (United States)

    Muniyan, Sakthivel; Chen, Siu-Ju; Lin, Fen-Fen; Wang, Zhengzhong; Mehta, Parmender P; Batra, Surinder K; Lin, Ming-Fong

    2015-11-01

    While androgen deprivation therapy (ADT) reduces tumor burden, autocrine growth factor loops such as human epidermal growth factor receptor 2 (HER2/ErbB-2/neu) have been proposed to contribute to prostate cancer (PCa) survival and relapse. However, the role of ErbB-2 in regulating androgen-sensitive (AS) and castration-resistant (CR) cell proliferation remains unclear. Here, we determined the role of ErbB-2 in PCa progression and survival under steroid-reduced conditions using two independent PCa cell progression models. In AR-positive androgen-independent (AI) PCa cells that exhibit the CR phenotype, ErbB-2 was constitutively activated, compared to corresponding AS PCa cells. In AS LNCaP C-33 cells, androgen-induced ErbB-2 activation through ERK1/2 mediates PCa cell proliferation. Further, the ErbB-2-specific but not EGFR-specific inhibitor suppresses basal and androgen-stimulated cell proliferation and also blocks ERK1/2 activation. ErbB-2 ectopic expression and cPAcP siRNA transfection of LNCaP C-33 cells each increases ErbB-2 tyrosine phosphorylation, correlating with increased AI PSA secretion and cell proliferation. Conversely, trapping ErbB-2 by transfected endoplasmic reticulum-targeting ScFv5R expression vector abolished DHT-induced LNCaP C-33 cell growth. Moreover, inhibition of ErbB-2 but not EGFR in AI LNCaP C-81 and MDA PCa2b-AI PCa cells significantly abolished AI cell growth. In contrast to androgens via ErbB-2/ERK1/2 signaling in AS PCa cells, the inhibition of ErbB-2 abrogated AI cell proliferation by inhibiting the cell survival protein Akt in those AI cells. These results suggest that ErbB-2 is a prominent player in mediating the ligand-dependent and -independent activation of AR in AS and AI/CR PCa cells respectively for PCa progression and survival. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. Multivalent Peptidomimetic Conjugates as Inhibitors of Androgen Receptor Function in Therapy-Resistant Prostate Cancer

    Science.gov (United States)

    2016-10-01

    Therapy-Resistant Prostate Cancer 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Kent Kirshenbaum, PhD 5d. PROJECT NUMBER 5e. TASK NUMBER...releasing hormone (LHRH) agonists that prevent testicular androgen synthesis or AR antagonists, such as bicalutamide (Casodex), which block AR...Prostate Cancer PRINCIPAL INVESTIGATOR: Kent Kirshenbaum CONTRACTING ORGANIZATION: New York University New York, NY 10012 REPORT DATE: October

  17. Multivalent Peptidomimetic Conjugates as Inhibitors of Androgen Receptor Function in Therapy Resistant Prostate Cancer

    Science.gov (United States)

    2016-10-01

    Receptor Function in Therapy-Resistant Prostate Cancer 5b. GRANT NUMBER W81XWH-15-1-0590 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Kendall W. Nettles... prevent testicular androgen synthesis or AR antagonists, such as bicalutamide (Casodex), which block AR transcriptional activity (3). Although...Prostate Cancer PRINCIPAL INVESTIGATOR: Dr. Kendall W. Nettles CONTRACTING ORGANIZATION: Scripps Research Institute, The Jupiter, FL 33458 REPORT DATE

  18. REST mediates androgen receptor actions on gene repression and predicts early recurrence of prostate cancer

    DEFF Research Database (Denmark)

    Svensson, Charlotte; Ceder, Jens; Iglesias Gato, Diego

    2014-01-01

    The androgen receptor (AR) is a key regulator of prostate tumorgenesis through actions that are not fully understood. We identified the repressor element (RE)-1 silencing transcription factor (REST) as a mediator of AR actions on gene repression. Chromatin immunoprecipitation showed that AR binds...

  19. Effects of recreational soccer in men with prostate cancer undergoing androgen deprivation therapy

    DEFF Research Database (Denmark)

    Uth, Jacob; Schmidt, Jakob Friis; Christensen, Jesper Frank

    2013-01-01

    Androgen deprivation therapy (ADT) is a cornerstone in the treatment of advanced prostate cancer. Adverse musculoskeletal and cardiovascular effects of ADT are widely reported and investigations into the potential of exercise to ameliorate the effects of treatment are warranted. The 'Football Club...

  20. Steroidogenic enzymes and stem cell markers are upregulated during androgen deprivation in prostate cancer

    NARCIS (Netherlands)

    Pfeiffer, M.J.; Smit, F.P.; Sedelaar, J.P.M.; Schalken, J.A.

    2011-01-01

    Considerable levels of testosterone and dihydrotestosterone (DHT) are found in prostate cancer (PCa) tissue after androgen deprivation therapy. Treatment of surviving cancer-initiating cells and the ability to metabolize steroids from precursors may be the keystones for the appearance of recurrent

  1. Refinement of the androgen response element based on ChIP-Seq in androgen-insensitive and androgen-responsive prostate cancer cell lines.

    Science.gov (United States)

    Wilson, Stephen; Qi, Jianfei; Filipp, Fabian V

    2016-09-14

    Sequence motifs are short, recurring patterns in DNA that can mediate sequence-specific binding for proteins such as transcription factors or DNA modifying enzymes. The androgen response element (ARE) is a palindromic, dihexameric motif present in promoters or enhancers of genes targeted by the androgen receptor (AR). Using chromatin immunoprecipitation sequencing (ChIP-Seq) we refined AR-binding and AREs at a genome-scale in androgen-insensitive and androgen-responsive prostate cancer cell lines. Model-based searches identified more than 120,000 ChIP-Seq motifs allowing for expansion and refinement of the ARE. We classified AREs according to their degeneracy and their transcriptional involvement. Additionally, we quantified ARE utilization in response to somatic copy number amplifications, AR splice-variants, and steroid treatment. Although imperfect AREs make up 99.9% of the motifs, the degree of degeneracy correlates negatively with validated transcriptional outcome. Weaker AREs, particularly ARE half sites, benefit from neighboring motifs or cooperating transcription factors in regulating gene expression. Taken together, ARE full sites generate a reliable transcriptional outcome in AR positive cells, despite their low genome-wide abundance. In contrast, the transcriptional influence of ARE half sites can be modulated by cooperating factors.

  2. Androgen receptor differentially regulates the proliferation of prostatic epithelial cells in vitro and in vivo

    Science.gov (United States)

    Grabowska, Magdalena M.; Li, Jiahe; Connelly, Zachary M.; Zhang, Jianghong; Hayward, Simon W.; Cates, Justin M.; Han, Guichun; Yu, Xiuping

    2016-01-01

    Androgens regulate the proliferation and differentiation of prostatic epithelial cells, including prostate cancer (PCa) cells in a context-dependent manner. Androgens and androgen receptor (AR) do not invariably promote cell proliferation; in the normal adult, endogenous stromal and epithelial AR activation maintains differentiation and inhibits organ growth. In the current study, we report that activation of AR differentially regulates the proliferation of human prostate epithelial progenitor cells, NHPrE1, in vitro and in vivo. Inducing AR signaling in NHPrE1 cells suppressed cell proliferation in vitro, concomitant with a reduction in MYC expression. However, ectopic expression of AR in vivo stimulated cell proliferation and induced development of invasive PCa in tissue recombinants consisting of NHPrE1/AR cells and rat urogenital mesenchymal (UGM) cells, engrafted under renal capsule of adult male athymic mice. Expression of MYC increased in the NHPrE1/AR recombinant tissues, in contrast to the reduction seen in vitro. The inhibitory effect of AR signaling on cell proliferation in vitro were reduced by co-culturing NHPrE1/AR epithelial cells with prostatic stromal cells. In conclusion, these studies revealed that AR signaling differentially regulates proliferation of human prostatic epithelia cells in vitro and in vivo through mechanisms involving stromal/epithelial interactions. PMID:27611945

  3. Radiotherapy and local hyperthermia plus androgen suppression in locally advanced prostate cancer

    International Nuclear Information System (INIS)

    Maluta, S.; Marciai, N.; Gabbani, M.; Palazzi, M.; Dall'Oglio, S.; Grandinetti, A.

    2005-01-01

    Full text: In advanced prostatic cancer, hyperthermia may be useful in order to enhance irradiation efficacy so to avoid delivering of too high dose of radiotherapy which increases acute and late sequelae. A multi-centric phase II study is warranted to give hyperthermia a level 3 evidence in prostate cancer treatment. A randomized phase III study to demonstrate efficacy of hyperthermia is not available because of the optimal results obtained by using radiotherapy combined with androgen suppression. To evaluate hyperthermia gain, LHT should be combined with radiotherapy alone in patients refusing androgen suppression or affected by hormone refractory prostate carcinoma (HRPC). Patients with HRPC have multiple possibilities of treatment improving performance status and median survival, as chemotherapy regimens, and new agents. All these treatments modalities need to be confirmed by phase III trials. Also hyperthermia may be considered among these promising approaches. (author)

  4. A precisely substituted benzopyran targets androgen refractory prostate cancer cells through selective modulation of estrogen receptors

    Energy Technology Data Exchange (ETDEWEB)

    Kumar, Rajeev; Verma, Vikas; Sharma, Vikas; Jain, Ashish; Singh, Vishal [Division of Endocrinology, CSIR—Central Drug Research Institute, Lucknow 226 031 (India); Sarswat, Amit [Division of Medicinal & Process Chemistry, CSIR—Central Drug Research Institute, Lucknow 226 031 (India); Maikhuri, Jagdamba P. [Division of Endocrinology, CSIR—Central Drug Research Institute, Lucknow 226 031 (India); Sharma, Vishnu L. [Division of Medicinal & Process Chemistry, CSIR—Central Drug Research Institute, Lucknow 226 031 (India); Gupta, Gopal, E-mail: g_gupta@cdri.res.in [Division of Endocrinology, CSIR—Central Drug Research Institute, Lucknow 226 031 (India)

    2015-03-15

    Dietary consumption of phytoestrogens like genistein has been linked with lower incidence of prostate cancer. The estradiol-like benzopyran core of genistein confers estrogen receptor-β (ER-β) selectivity that imparts weak anti-proliferative activity against prostate cancer cells. DL-2-[4-(2-piperidinoethoxy)phenyl]-3-phenyl-2H-1-benzopyran (BP), a SERM designed with benzopyran core, targeted androgen independent prostate cancer (PC-3) cells 14-times more potently than genistein, ~ 25% more efficiently than tamoxifen and 6.5-times more actively than ICI-182780, without forfeiting significant specificity in comparison to genistein. BP increased apoptosis (annexin-V and TUNEL labeling), arrested cell cycle, and significantly increased caspase-3 activity along with mRNA expressions of estrogen receptor (ER)-β and FasL (qPCR) in PC-3 cells. In classical ERE-luc reporter assay BP behaved as a potent ER-α antagonist and ER-β agonist. Accordingly, it decreased expression of ER-α target PS2 (P < 0.01) and increased expression of ER-β target TNF-α (P < 0.05) genes in PC-3. ER-β deficient PC-3 (siRNA-transfected) was resistant to apoptotic and anti-proliferative actions of SERMs, including stimulation of FasL expression by BP. BP significantly inhibited phosphorylation of Akt and ERK-1/2, JNK and p38 in PC-3 (immunoblotting), and thus adopted a multi-pathway mechanism to exert a more potent anti-proliferative activity against prostate cancer cells than natural and synthetic SERMs. Its precise ER-subtype specific activity presents a unique lead structure for further optimization. - Highlights: • BP with benzopyran core of genistein was identified for ER-β selective action. • BP was 14-times more potent than genistien in targeting prostate cancer cells. • It behaved as a potent ER-β agonist and ER-α antagonist in gene reporter assays. • BP's anti-proliferative action was inhibited significantly in ER-β deficient cells. • BP — a unique lead

  5. New Prostate Cancer Treatment Target

    Science.gov (United States)

    Researchers have identified a potential alternative approach to blocking a key molecular driver of an advanced form of prostate cancer, called androgen-independent or castration-resistant prostate cancer.

  6. Sox2 is an androgen receptor-repressed gene that promotes castration-resistant prostate cancer.

    Directory of Open Access Journals (Sweden)

    Steven Kregel

    Full Text Available Despite advances in detection and therapy, castration-resistant prostate cancer continues to be a major clinical problem. The aberrant activity of stem cell pathways, and their regulation by the Androgen Receptor (AR, has the potential to provide insight into novel mechanisms and pathways to prevent and treat advanced, castrate-resistant prostate cancers. To this end, we investigated the role of the embryonic stem cell regulator Sox2 [SRY (sex determining region Y-box 2] in normal and malignant prostate epithelial cells. In the normal prostate, Sox2 is expressed in a portion of basal epithelial cells. Prostate tumors were either Sox2-positive or Sox2-negative, with the percentage of Sox2-positive tumors increasing with Gleason Score and metastases. In the castration-resistant prostate cancer cell line CWR-R1, endogenous expression of Sox2 was repressed by AR signaling, and AR chromatin-IP shows that AR binds the enhancer element within the Sox2 promoter. Likewise, in normal prostate epithelial cells and human embryonic stem cells, increased AR signaling also decreases Sox2 expression. Resistance to the anti-androgen MDV3100 results in a marked increase in Sox2 expression within three prostate cancer cell lines, and in the castration-sensitive LAPC-4 prostate cancer cell line ectopic expression of Sox2 was sufficient to promote castration-resistant tumor formation. Loss of Sox2 expression in the castration-resistant CWR-R1 prostate cancer cell line inhibited cell growth. Up-regulation of Sox2 was not associated with increased CD133 expression but was associated with increased FGF5 (Fibroblast Growth Factor 5 expression. These data propose a model of elevated Sox2 expression due to loss of AR-mediated repression during castration, and consequent castration-resistance via mechanisms not involving induction of canonical embryonic stem cell pathways.

  7. Do androgens control the uptake of {sup 18}F-FDG, {sup 11}C-choline and {sup 11}C-acetate in human prostate cancer cell lines?

    Energy Technology Data Exchange (ETDEWEB)

    Emonds, Kimy M.; Nuyts, Johan; Mortelmans, Luc [University Hospital Gasthuisberg Leuven, Department of Nuclear Medicine, Leuven (Belgium); Swinnen, Johannes V.; Vanderhoydonc, Frank [K.U. Leuven, Laboratory for Experimental Medicine and Endocrinology, Department of Experimental Medicine, Leuven (Belgium); Weerden, Wytske M. van [Erasmus University Rotterdam, Department of Experimental Urology, Josephine Nefkens Institute, Rotterdam (Netherlands); Mottaghy, Felix M. [University Hospital Gasthuisberg Leuven, Department of Nuclear Medicine, Leuven (Belgium); University Hospital Aachen, Department of Nuclear Medicine, Aachen (Germany); Maastricht University Medical Center, Department of Nuclear Medicine, Maastricht (Netherlands)

    2011-10-15

    The aim of this study was to evaluate the impact of androgen ablation therapy in different prostate cancer (PCa) cell lines - reflecting different stages of the disease - on {sup 18}F-fluorodeoxyglucose (FDG), {sup 11}C-choline and {sup 11}C-acetate uptake. Uptake experiments were performed in androgen-sensitive (LNCaP, PC346C) and independent cell lines (22Rv1, PC346DCC, PC-3) as well as in a benign prostatic hyperplasia (BPH-1) cell line. Tracer uptake was assessed under androgen ablation. Results of the cancer cell lines were normalized to those of BPH-1. To evaluate the effect of androgen on the uptake of {sup 18}F-FDG, {sup 11}C-choline and {sup 11}C-acetate in PCa cell lines, 10{sup -8}M R1881, 10{sup -10}M R1881, the combination of 10{sup -10}M R1881 plus 10{sup -6}M Casodex or 10{sup -6}M Casodex alone were added in parallel cell cultures 1 day before uptake experiments. Uptake in androgen-supplemented cell cultures was compared to the uptake under androgen deprivation. Uptake was corrected for cell number using protein content. Compared to BPH-1, a higher {sup 18}F-FDG uptake was observed only in PC346C cells, whereas a higher {sup 11}C-choline and markedly increased {sup 11}C-acetate uptake was seen in all cancer cell lines. Androgens significantly modulated the uptake of {sup 18}F-FDG in LNCaP, PC346C and 22Rv1 cells, and of {sup 11}C-choline in the PC346C and 22Rv1 cell line. No androgenic effect on {sup 11}C-choline and {sup 18}F-FDG uptake was observed in PC-3 and PC346DCC cells. {sup 11}C-Acetate uptake was independent of androgen status in all PCa cell lines studied. {sup 18}F-FDG uptake in PCa cell lines showed the highest variability and strongest androgen effect, suggesting its poor potential for metabolic imaging of advanced PCa. In contrast to {sup 18}F-FDG and {sup 11}C-choline, {sup 11}C-acetate uptake was unaffected by androgens and thus {sup 11}C-acetate seems best for monitoring PCa progression. (orig.)

  8. TRPM8 channel as a novel molecular target in androgen-regulated prostate cancer cells.

    Science.gov (United States)

    Asuthkar, Swapna; Velpula, Kiran Kumar; Elustondo, Pia A; Demirkhanyan, Lusine; Zakharian, Eleonora

    2015-07-10

    The cold and menthol receptor TRPM8 is highly expressed in prostate and prostate cancer (PC). Recently, we identified that TRPM8 is as an ionotropic testosterone receptor. The TRPM8 mRNA is expressed in early prostate tumors with high androgen levels, while anti-androgen therapy greatly reduces its expression. Here, from the chromatin-immunoprecipitation (ChIP) analysis, we found that an androgen response element (ARE) mediates androgen regulation of trpm8. Furthermore, using immunofluorescence, calcium-imaging and planar lipid bilayers, we identified that TRPM8 channel is functionally regulated by androgens in the prostate. Although TRPM8 mRNA is expressed at high levels, we found that the TRPM8 protein undergoes ubiquitination and degradation in PC cells. The mass-spectrometry analysis of TRPM8, immunoprecipitated from LNCaP cells identified ubiquitin-like modifier-activating enzyme 1 (UBA1). PYR-41, a potent inhibitor of initial enzyme in the ubiquitination cascade, UBA1, increased TRPM8 activity on the plasma membrane (PM) of LNCaP cells. Furthermore, PYR-41-mediated PMTRPM8 activity was accompanied by enhanced activation of p53 and Caspase-9. Interestingly, we found that the trpm8 promoter possesses putative binding sites for p53 and that the overexpression of p53 increased the TRPM8 mRNA levels. In addition to the genomic regulation of TRPM8 by AR and p53, our findings indicate that the testosterone-induced PMTRPM8 activity elicits Ca2+ uptake, subsequently causing apoptotic cell death. These findings support the strategy of rescuing PMTRPM8 expression as a new therapeutic application through the regulation of PC cell growth and proliferation.

  9. Disruption of the Interaction of the Androgen Receptor with Chromatin: A Novel Therapeutic Approach in Prostate Cancer

    Science.gov (United States)

    2016-10-01

    average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and...level. KEYWORDS: Prostate cancer, Androgen Receptor, FOXA1, androgen receptor co- regulators , Protein-protein interactions, peptides...study the interaction between overexpressed AR and FOXA1. This assay system facilitates the validation experiments of

  10. Intermittent androgen deprivation therapy in patients with prostate cancer: Connecting the dots

    Directory of Open Access Journals (Sweden)

    Per-Anders Abrahamsson

    2017-10-01

    Full Text Available Intermittent androgen deprivation therapy (IADT is now being increasingly opted by the treating physicians and patients with prostate cancer. The most common reason driving this is the availability of an off-treatment period to the patients that provides some relief from treatment-related side-effects, and reduced treatment costs. IADT may also delay the progression to castration-resistant prostate cancer. However, the use of IADT in the setting of prostate cancer has not been strongly substantiated by data from clinical trials. Multiple factors seem to contribute towards this inadequacy of supportive data for the use of IADT in patients with prostate cancer, e.g., population characteristics (both demographic and clinical, study design, treatment regimen, on- and off-treatment criteria, duration of active treatment, endpoints, and analysis. The present review article focuses on seven clinical trials that evaluated the efficacy of IADT vs. continuous androgen deprivation therapy for the treatment of prostate cancer. The results from these clinical trials have been discussed in light of the factors that may impact the treatment outcomes, especially the disease (tumor burden. Based on evidence, potential candidate population for IADT has been suggested along with recommendations for the use of IADT in patients with prostate cancer.

  11. Hydrolysis of androgen receptor by cathepsin D: its biological significance in human prostate cancer.

    Science.gov (United States)

    Mordente, J A; Choudhury, M S; Tazaki, H; Mallouh, C; Konno, S

    1998-09-01

    To elicit the biological role of a lysosomal protease, cathepsin D (CatD) in prostate cancer, by investigating its regulatory effect on the androgen receptor (AR) using human prostate cancer LNCaP cells and prostate tissue specimens. Cell extracts were prepared from LNCaP or prostate specimens by cell lysis and tissue homogenization. Proteolytic assays were performed by incubating these extracts in acidic buffer (pH 3-4) at 37 degrees C. The resulting effects on AR and CatD were then analysed using Western immunoblots. The Western blots showed that AR was virtually hydrolysed with acid treatment, because endogenous CatD was activated; this activation only occurred at pH 3.2-3.5, but no specific acid appeared to be required. Further analyses suggested that CatD activation could be attributed to acid-induced autoproteolysis of mature CatD. Similar assays were also performed on prostate tissues, including normal and malignant specimens. These studies revealed that CatD-mediated AR hydrolysis was observed only in cancer specimens, while no such hydrolysis occurred in normal specimens. Endogenous CatD can hydrolyse AR, thereby possibly modulating AR function/metabolism in LNCaP cells, and in cancer specimens. CatD activity also appears to differ significantly between normal and malignant tissue. Thus, CatD may play a pivotal role as a growth modulator in androgen-dependent prostate cancer.

  12. Inhibition of androgen receptor by decoy molecules delays progression to castration-recurrent prostate cancer.

    Directory of Open Access Journals (Sweden)

    Jae-Kyung Myung

    Full Text Available Androgen receptor (AR is a member of the steroid receptor family and a therapeutic target for all stages of prostate cancer. AR is activated by ligand binding within its C-terminus ligand-binding domain (LBD. Here we show that overexpression of the AR NTD to generate decoy molecules inhibited both the growth and progression of prostate cancer in castrated hosts. Specifically, it was shown that lentivirus delivery of decoys delayed hormonal progression in castrated hosts as indicated by increased doubling time of tumor volume, prolonged time to achieve pre-castrate levels of serum prostate-specific antigen (PSA and PSA nadir. These clinical parameters are indicative of delayed hormonal progression and improved therapeutic response and prognosis. Decoys reduced the expression of androgen-regulated genes that correlated with reduced in situ interaction of the AR with androgen response elements. Decoys did not reduce levels of AR protein or prevent nuclear localization of the AR. Nor did decoys interact directly with the AR. Thus decoys did not inhibit AR transactivation by a dominant negative mechanism. This work provides evidence that the AR NTD plays an important role in the hormonal progression of prostate cancer and supports the development of AR antagonists that target the AR NTD.

  13. The therapeutic effects of docosahexaenoic acid on oestrogen/androgen-induced benign prostatic hyperplasia in rats

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Chao [Department of Biochemistry and Molecular Biology, College of Life Sciences, Bioactive Materials Key Lab of Ministry of Education, Nankai University, Tianjin 300071 (China); Luo, Fei [Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin Institute of Urology, Tianjin 300211 (China); Zhou, Ying; Du, Xiaoling; Shi, Jiandang; Zhao, Xiaoling [Department of Biochemistry and Molecular Biology, College of Life Sciences, Bioactive Materials Key Lab of Ministry of Education, Nankai University, Tianjin 300071 (China); Xu, Yong [Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin Institute of Urology, Tianjin 300211 (China); Zhu, Yan [Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193 (China); Hong, Wei, E-mail: hongwei@tijmu.edu.cn [Department of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070 (China); Zhang, Ju, E-mail: zhangju@nankai.edu.cn [Department of Biochemistry and Molecular Biology, College of Life Sciences, Bioactive Materials Key Lab of Ministry of Education, Nankai University, Tianjin 300071 (China)

    2016-07-15

    Benign prostatic hyperplasia (BPH) is one of the major disorders of the urinary system in elderly men. Docosahexaenoic acid (DHA) is the main component of n-3 polyunsaturated fatty acids (n-3 PUFAs) and has nerve protective, anti-inflammatory and tumour-growth inhibitory effects. Here, the therapeutic potential of DHA in treating BPH was investigated. Seal oil effectively prevented the development of prostatic hyperplasia induced by oestradiol/testosterone in a rat model by suppressing the increase of the prostatic index (PI), reducing the thickness of the peri-glandular smooth muscle layer, inhibiting the proliferation of both prostate epithelial and stromal cells, and downregulating the expression of androgen receptor (AR) and oestrogen receptor α (ERα). An in vitro study showed that DHA inhibited the growth of the human prostate stromal cell line WPMY-1 and the epithelial cell line RWPE-1 in a dose- and time-dependent manner. In both cell lines, the DHA arrested the cell cycle in the G2/M phase. In addition, DHA also reduced the expression of ERα and AR in the WPMY-1 and RWPE-1 cells. These results indicate that DHA inhibits the multiplication of prostate stromal and epithelial cells through a mechanism that may involve cell cycle arrest and the downregulation of ERα and AR expression. - Highlights: • Seal oil prevents oestradiol/testosterone (E2/T)-induced BPH in castrated rats. • Seal oil downregulates the expression of oestrogen receptor α(ERα) and androgen receptor (AR) in rat BPH tissues. • DHA inhibits the growth of human prostate stromal and epithelial cells in vitro. • DHA arrests human prostate stromal and epithelial cells in the G2/M phase and downregulates the expression of cyclin B1. • DHA inhibits the expression of ERα and AR in human prostate stromal and epithelial cells.

  14. Increase in visceral and subcutaneous abdominal fat in men with prostate cancer treated with androgen deprivation therapy.

    Science.gov (United States)

    Hamilton, E J; Gianatti, E; Strauss, B J; Wentworth, J; Lim-Joon, D; Bolton, D; Zajac, J D; Grossmann, M

    2011-03-01

    Androgen deprivation therapy (ADT) for prostate cancer is associated with increases in fat mass and risk of type 2 diabetes; however, the relationship between sex steroid deficiency and abdominal fat distribution remains controversial. We conducted a 12-month prospective observational study at a tertiary referral centre. We investigated changes in abdominal fat distribution and insulin resistance in 26 men (70.6±6.8 years) with nonmetastatic prostate cancer during the first year of ADT. Twelve months of ADT increased visceral abdominal fat area by 22% (from 160.8±61.7 to 195.9±69.7 cm(2) ; Pfat area by 13% (from 240.7±107.5 to 271.3±92.8 cm(2) ; PFat mass increased by 14% (+3.4 kg; Ptestosterone (TT) was inversely associated with visceral fat area independent of oestradiol (E2), but E2 was not associated with visceral fat area independent of TT. Visceral fat area, not TT or E2, was independently associated with insulin resistance. ADT for prostate cancer results in accumulation of both visceral and subcutaneous abdominal fat. Increased visceral fat area appears more closely linked to testosterone than oestradiol deficiency. Increased insulin resistance may arise secondary to visceral fat accumulation, rather than as a direct result of sex steroid deficiency. © 2011 Blackwell Publishing Ltd.

  15. Amino acid containing thapsigargin analogues deplete androgen receptor protein via synthesis inhibition and induce the death of prostate cancer cells

    DEFF Research Database (Denmark)

    Griend, Donald J Vander; Antony, Lizamma; Dalrymple, Susan L

    2009-01-01

    There are quantitative and/or qualitative mechanisms allowing androgen receptor (AR) growth signaling in androgen ablation refractory prostate cancer cells. Regardless of the mechanism, agents that deplete AR protein expression prevent such AR growth signaling. Thapsigargin (TG) is a highly cell......-penetrant sequiterpene-lactone that once inside cells inhibits (IC(50), approximately 10 nmol/L) critically important housekeeping SERCA 2b calcium pumps in the endoplasmic reticulum. Using a series of five genetically diverse androgen ablation refractory human prostate cancer lines (LNCaP, LAPC-4, VCaP, MDA-PCa-2b......-specific proteases, such as prostate-specific antigen and prostate-specific membrane antigen, or cancer-specific proteases, such as fibroblast activation protein, so that toxicity of these prodrugs is selectively targeted to metastatic sites of prostate cancer. Based on these results, these prodrugs are undergoing...

  16. Familial prostate cancer: outcome following radiation therapy with or without adjuvant androgen ablation

    International Nuclear Information System (INIS)

    Hanus, Michael C.; Zagars, Gunar K.; Pollack, Alan

    1999-01-01

    Purpose: To compare the outcome of familial versus sporadic prostate carcinoma after definitive external radiation. Methods and Materials: Between 1987 and 1996, 1214 men with clinically localized prostate cancer (T1-T4, N0/NX, M0) received definitive radiation therapy in our department. By retrospective review of charts and questioning of patients, a record on the presence or absence of prostate cancer in a first degree relative was obtained in 1164 men. Univariate and multivariate analysis was performed on these cases with relapse or rising prostate-specific antigen (PSA), local recurrence, metastasis, and survival as endpoints. Results: Familiar prostate cancer was present in 148 of 1164 men (13%). Men with familial disease were slightly but significantly younger (mean 66 years) at diagnosis than those with sporadic disease (mean 68 years) (p = 0.02). Apart from this there were no significant differences between the two groups in T-stage, Gleason score, pretreatment PSA levels, DNA ploidy, or serum testosterone levels. There were no significant differences in treatment parameters including radiation dose and the use of adjuvant androgen ablation. With a median follow-up of 42 months, there was no difference in freedom from relapse or rising PSA at 6 years between those with a family history (54%) and those without a family history (58%) (p = 0.171). Likewise there was no difference between the two groups when local recurrence or metastasis was the endpoint. Multiple subgroup analyses (younger and older; T1/T2 and T3; low Gleason and high Gleason; no androgen ablation and androgen ablation; race) failed to reveal any differences in outcome in any category between familial and sporadic disease. Among patients with a rising post-treatment PSA profile, PSA doubling times were similar in those with sporadic and familial disease. Conclusions: This study provides no evidence for any substantial difference between familial and sporadic prostate cancer either in

  17. Effects of Sorafenib on C-Terminally Truncated Androgen Receptor Variants in Human Prostate Cancer Cells

    Directory of Open Access Journals (Sweden)

    Mark Schrader

    2012-09-01

    Full Text Available Recent evidence suggests that the development of castration resistant prostate cancer (CRPCa is commonly associated with an aberrant, ligand-independent activation of the androgen receptor (AR. A putative mechanism allowing prostate cancer (PCa cells to grow under low levels of androgens, is the expression of constitutively active, C-terminally truncated AR lacking the AR-ligand binding domain (LBD. Due to the absence of a LBD, these receptors, termed ARΔLBD, are unable to respond to any form of anti-hormonal therapies. In this study we demonstrate that the multikinase inhibitor sorafenib inhibits AR as well as ARΔLBD-signalling in CRPCa cells. This inhibition was paralleled by proteasomal degradation of the AR- and ARΔLBD-molecules. In line with these observations, maximal antiproliferative effects of sorafenib were achieved in AR and ARΔLBD-positive PCa cells. The present findings warrant further investigations on sorafenib as an option for the treatment of advanced AR-positive PCa.

  18. Effect of small molecules modulating androgen receptor (SARMs in human prostate cancer models.

    Directory of Open Access Journals (Sweden)

    Anna Tesei

    Full Text Available The management of hormone-refractory prostate cancer represents a major challenge in the therapy of this tumor, and identification of novel androgen receptor antagonists is needed to render treatment more effective. We analyzed the activity of two novel androgen receptor antagonists, (S-11 and (R-9, in in vitro and in vivo experimental models of hormone-sensitive or castration-resistant prostate cancer (CRPC. In vitro experiments were performed on LNCaP, LNCaP-AR, LNCaP-Rbic and VCaP human prostate cancer cells. Cytotoxic activity was assessed by SRB and BrdU uptake, AR transactivation by luciferase reporter assay and PSA levels by Real Time RT-PCR and ELISA assays. Cell cycle progression-related markers were evaluated by western blot. In vivo experiments were performed on SCID mice xenografted with cells with different sensitivity to hormonal treatment. In hormone-sensitive LNCaP and LNCaP-AR cells, the latter expressing high androgen receptor levels, (R-9 and (S-11 exhibited a higher cytotoxic effect compared to that of the reference compound ((R-bicalutamide, also in the presence of the synthetic androgen R1881. Furthermore, the cytotoxic effect produced by (R-9 was higher than that of (S-11 in the two hormone-resistant LNCaP-AR and VCaP cells. A significant reduction in PSA levels was observed after exposure to both molecules. Moreover, (S-11 and (R-9 inhibited DNA synthesis by blocking the androgen-induced increase in cyclin D1 protein levels. In vivo studies on the toxicological profile of (R-9 did not reveal the presence of adverse events. Furthermore, (R-9 inhibited tumor growth in various in vivo models, especially LNCaP-Rbic xenografts, representative of recurrent disease. Our in vitro results highlight the antitumor activity of the two novel molecules (R-9 and (S-11, making them a potentially attractive option for the treatment of CRPC.

  19. Effect of small molecules modulating androgen receptor (SARMs) in human prostate cancer models.

    Science.gov (United States)

    Tesei, Anna; Leonetti, Carlo; Di Donato, Marzia; Gabucci, Elisa; Porru, Manuela; Varchi, Greta; Guerrini, Andrea; Amadori, Dino; Arienti, Chiara; Pignatta, Sara; Paganelli, Giulia; Caraglia, Michele; Castoria, Gabriella; Zoli, Wainer

    2013-01-01

    The management of hormone-refractory prostate cancer represents a major challenge in the therapy of this tumor, and identification of novel androgen receptor antagonists is needed to render treatment more effective. We analyzed the activity of two novel androgen receptor antagonists, (S)-11 and (R)-9, in in vitro and in vivo experimental models of hormone-sensitive or castration-resistant prostate cancer (CRPC). In vitro experiments were performed on LNCaP, LNCaP-AR, LNCaP-Rbic and VCaP human prostate cancer cells. Cytotoxic activity was assessed by SRB and BrdU uptake, AR transactivation by luciferase reporter assay and PSA levels by Real Time RT-PCR and ELISA assays. Cell cycle progression-related markers were evaluated by western blot. In vivo experiments were performed on SCID mice xenografted with cells with different sensitivity to hormonal treatment. In hormone-sensitive LNCaP and LNCaP-AR cells, the latter expressing high androgen receptor levels, (R)-9 and (S)-11 exhibited a higher cytotoxic effect compared to that of the reference compound ((R)-bicalutamide), also in the presence of the synthetic androgen R1881. Furthermore, the cytotoxic effect produced by (R)-9 was higher than that of (S)-11 in the two hormone-resistant LNCaP-AR and VCaP cells. A significant reduction in PSA levels was observed after exposure to both molecules. Moreover, (S)-11 and (R)-9 inhibited DNA synthesis by blocking the androgen-induced increase in cyclin D1 protein levels. In vivo studies on the toxicological profile of (R)-9 did not reveal the presence of adverse events. Furthermore, (R)-9 inhibited tumor growth in various in vivo models, especially LNCaP-Rbic xenografts, representative of recurrent disease. Our in vitro results highlight the antitumor activity of the two novel molecules (R)-9 and (S)-11, making them a potentially attractive option for the treatment of CRPC.

  20. Obstructing Androgen Receptor Activation in Prostate Cancer Cells Through Post-translational Modification by NEDD8

    Science.gov (United States)

    2011-05-01

    The overall goal of this study is to investigate the effect of post-translational NEDD8 modification on androgen receptor. In year 3, we proposed to establish Jab1 shRNA expressing lines of prostate cancer cells and to characterize the effects of Jab1 silencing on prostate cancer cell growth and proliferation. Several stable cell lines have been established, and experiments are being conducted to characterize these cell lines. These works are currently being continued into the final no-cost extension year.

  1. Preferred treatment frequency in patients receiving androgen deprivation therapy for advanced prostate cancer

    DEFF Research Database (Denmark)

    Fode, Mikkel; Nielsen, Torben K; Al-Hamadani, Muhammad

    2014-01-01

    OBJECTIVE: The aim of this study was to assess patient preference regarding the length of treatment intervals of androgen deprivation therapy (ADT) with gonadotropin-releasing hormone agonists for prostate cancer. MATERIAL AND METHODS: The study was conducted as a questionnaire-based, cross...... satisfaction and side-effects. Overall, 238 men receiving ADT for prostate cancer were presented with the questionnaire between September 2011 and May 2012. Descriptive statistics, the chi-squared test and multiple regression were used for analyses. RESULTS: In total, 176 questionnaires (74%) were available...

  2. Can Mathematical Models Predict the Outcomes of Prostate Cancer Patients Undergoing Intermittent Androgen Deprivation Therapy?

    Science.gov (United States)

    Everett, R. A.; Packer, A. M.; Kuang, Y.

    Androgen deprivation therapy is a common treatment for advanced or metastatic prostate cancer. Like the normal prostate, most tumors depend on androgens for proliferation and survival but often develop treatment resistance. Hormonal treatment causes many undesirable side effects which significantly decrease the quality of life for patients. Intermittently applying androgen deprivation in cycles reduces the total duration with these negative effects and may reduce selective pressure for resistance. We extend an existing model which used measurements of patient testosterone levels to accurately fit measured serum prostate specific antigen (PSA) levels. We test the model's predictive accuracy, using only a subset of the data to find parameter values. The results are compared with those of an existing piecewise linear model which does not use testosterone as an input. Since actual treatment protocol is to re-apply therapy when PSA levels recover beyond some threshold value, we develop a second method for predicting the PSA levels. Based on a small set of data from seven patients, our results showed that the piecewise linear model produced slightly more accurate results while the two predictive methods are comparable. This suggests that a simpler model may be more beneficial for a predictive use compared to a more biologically insightful model, although further research is needed in this field prior to implementing mathematical models as a predictive method in a clinical setting. Nevertheless, both models are an important step in this direction.

  3. Bone stroma-derived cells change coregulators recruitment to androgen receptor and decrease cell proliferation in androgen-sensitive and castration-resistant prostate cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Villagran, Marcelo A.; Gutierrez-Castro, Francisco A.; Pantoja, Diego F.; Alarcon, Jose C.; Fariña, Macarena A.; Amigo, Romina F.; Muñoz-Godoy, Natalia A. [Molecular Endocrinology and Oncology Laboratory, University of Concepcion, Concepcion (Chile); Pinilla, Mabel G. [Department of Medical Specialties, School of Medicine, University of Concepcion, Concepcion (Chile); Peña, Eduardo A.; Gonzalez-Chavarria, Ivan; Toledo, Jorge R.; Rivas, Coralia I.; Vera, Juan C. [Department of Physiopathology, School of Biological Sciences, University of Concepcion, Concepcion (Chile); McNerney, Eileen M. [Molecular Endocrinology and Oncology Laboratory, University of Concepcion, Concepcion (Chile); Onate, Sergio A., E-mail: sergio.onate@udec.cl [Molecular Endocrinology and Oncology Laboratory, University of Concepcion, Concepcion (Chile); Department of Medical Specialties, School of Medicine, University of Concepcion, Concepcion (Chile); Department of Urology, State University of New York at Buffalo, NY (United States)

    2015-11-27

    Prostate cancer (CaP) bone metastasis is an early event that remains inactive until later-stage progression. Reduced levels of circulating androgens, due to andropause or androgen deprivation therapies, alter androgen receptor (AR) coactivator expression. Coactivators shift the balance towards enhanced AR-mediated gene transcription that promotes progression to androgen-resistance. Disruptions in coregulators may represent a molecular switch that reactivates latent bone metastasis. Changes in AR-mediated transcription in androgen-sensitive LNCaP and androgen-resistant C4-2 cells were analyzed for AR coregulator recruitment in co-culture with Saos-2 and THP-1. The Saos-2 cell line derived from human osteosarcoma and THP-1 cell line representing human monocytes were used to display osteoblast and osteoclast activity. Increased AR activity in androgen-resistant C4-2 was due to increased AR expression and SRC1/TIF2 recruitment and decreased SMRT/NCoR expression. AR activity in both cell types was decreased over 90% when co-cultured with Saos-2 or THP-1 due to dissociation of AR from the SRC1/TIF2 and SMRT/NCoR coregulators complex, in a ligand-dependent and cell-type specific manner. In the absence of androgens, Saos-2 decreased while THP-1 increased proliferation of LNCaP cells. In contrast, both Saos-2 and THP-1 decreased proliferation of C4-2 in absence and presence of androgens. Global changes in gene expression from both CaP cell lines identified potential cell cycle and androgen regulated genes as mechanisms for changes in cell proliferation and AR-mediated transactivation in the context of bone marrow stroma cells. - Highlights: • Decreased corepressor expression change AR in androgen-resistance prostate cancer. • Bone stroma-derived cells change AR coregulator recruitment in prostate cancer. • Bone stroma cells change cell proliferation in androgen-resistant cancer cells. • Global gene expression in CaP cells is modified by bone stroma cells in co

  4. Bone stroma-derived cells change coregulators recruitment to androgen receptor and decrease cell proliferation in androgen-sensitive and castration-resistant prostate cancer cells

    International Nuclear Information System (INIS)

    Villagran, Marcelo A.; Gutierrez-Castro, Francisco A.; Pantoja, Diego F.; Alarcon, Jose C.; Fariña, Macarena A.; Amigo, Romina F.; Muñoz-Godoy, Natalia A.; Pinilla, Mabel G.; Peña, Eduardo A.; Gonzalez-Chavarria, Ivan; Toledo, Jorge R.; Rivas, Coralia I.; Vera, Juan C.; McNerney, Eileen M.; Onate, Sergio A.

    2015-01-01

    Prostate cancer (CaP) bone metastasis is an early event that remains inactive until later-stage progression. Reduced levels of circulating androgens, due to andropause or androgen deprivation therapies, alter androgen receptor (AR) coactivator expression. Coactivators shift the balance towards enhanced AR-mediated gene transcription that promotes progression to androgen-resistance. Disruptions in coregulators may represent a molecular switch that reactivates latent bone metastasis. Changes in AR-mediated transcription in androgen-sensitive LNCaP and androgen-resistant C4-2 cells were analyzed for AR coregulator recruitment in co-culture with Saos-2 and THP-1. The Saos-2 cell line derived from human osteosarcoma and THP-1 cell line representing human monocytes were used to display osteoblast and osteoclast activity. Increased AR activity in androgen-resistant C4-2 was due to increased AR expression and SRC1/TIF2 recruitment and decreased SMRT/NCoR expression. AR activity in both cell types was decreased over 90% when co-cultured with Saos-2 or THP-1 due to dissociation of AR from the SRC1/TIF2 and SMRT/NCoR coregulators complex, in a ligand-dependent and cell-type specific manner. In the absence of androgens, Saos-2 decreased while THP-1 increased proliferation of LNCaP cells. In contrast, both Saos-2 and THP-1 decreased proliferation of C4-2 in absence and presence of androgens. Global changes in gene expression from both CaP cell lines identified potential cell cycle and androgen regulated genes as mechanisms for changes in cell proliferation and AR-mediated transactivation in the context of bone marrow stroma cells. - Highlights: • Decreased corepressor expression change AR in androgen-resistance prostate cancer. • Bone stroma-derived cells change AR coregulator recruitment in prostate cancer. • Bone stroma cells change cell proliferation in androgen-resistant cancer cells. • Global gene expression in CaP cells is modified by bone stroma cells in co

  5. Exponential rise in prostate-specific antigen (PSA) during anti-androgen withdrawal predicts PSA flare after docetaxel chemotherapy in patients with castration-resistant prostate cancer.

    Science.gov (United States)

    Han, Kyung Seok; Hong, Sung Joon

    2015-03-01

    To investigate the relationship between rising patterns of prostate-specific antigen (PSA) before chemotherapy and PSA flare during the early phase of chemotherapy in patients with castration-resistant prostate cancer (CRPC). This study included 55 patients with CRPC who received chemotherapy and in whom pre-treatment or post-treatment PSA levels could be serially obtained. The baseline parameters included age, performance, Gleason score, PSA level, and disease extent. PSA doubling time was calculated using the different intervals: the conventional interval from the second hormone manipulation following the nadir until anti-androgen withdrawal (PSADT1), the interval from the initial rise after anti-androgen withdrawal to the start of chemotherapy (PSADT2), and the interval from the nadir until the start of chemotherapy (PSADT3). The PSA growth patterns were analyzed using the ratio of PSADT2 to PSADT1. There were two growth patterns of PSA doubling time: 22 patients (40.0%) had a steady pattern with a more prolonged PSADT2 than PSADT1, while 33 (60.0%) had an accelerating pattern with a shorter PSADT2 than PSADT1. During three cycles of chemotherapy, PSA flare occurred in 11 patients (20.0%); of these patients, 3 were among 33 (9.1%) patients with an accelerating PSA growth pattern and 8 were among 22 patients (36.4%) with a steady PSA growth pattern (p=0.019). Multivariate analysis showed that only PSA growth pattern was an independent predictor of PSA flare (p=0.034). An exponential rise in PSA during anti-androgen withdrawal is a significant predictor for PSA flare during chemotherapy in CRPC patients.

  6. A novel selective androgen receptor modulator (SARM) MK-4541 exerts anti-androgenic activity in the prostate cancer xenograft R-3327G and anabolic activity on skeletal muscle mass & function in castrated mice.

    Science.gov (United States)

    Chisamore, Michael J; Gentile, Michael A; Dillon, Gregory Michael; Baran, Matthew; Gambone, Carlo; Riley, Sean; Schmidt, Azriel; Flores, Osvaldo; Wilkinson, Hilary; Alves, Stephen E

    2016-10-01

    The androgen receptor (AR) is a member of the nuclear hormone receptor super family of transcription factors. Androgens play an essential role in the development, growth, and maintenance of male sex organs, as well as the musculoskeletal and central nervous systems. Yet with advancing age, androgens can drive the onset of prostate cancer, the second leading cause of cancer death in males within the United States. Androgen deprivation therapy (ADT) by pharmacologic and/or surgical castration induces apoptosis of prostate cells and subsequent shrinkage of the prostate and prostate tumors. However, ADT is associated with significant musculoskeletal and behavioral adverse effects. The unique pharmacological activity of selective androgen receptor modulator (SARM) MK-4541 recently has been reported as an AR antagonist with 5α-reductase inhibitor function. The molecule inhibits proliferation and induces apoptosis in AR positive, androgen dependent prostate cancer cells. Importantly, MK-4541 inhibited androgen-dependent prostate growth in male rats yet maintained lean body mass and bone formation following ovariectomy in female rats. In the present study, we evaluated the effects of SARM MK-4541 in the androgen-dependent Dunning R3327-G prostate carcinoma xenograft mouse model as well as on skeletal muscle mass and function, and AR-regulated behavior in mice. MK-4541 significantly inhibited the growth of R3327-G prostate tumors, exhibited anti-androgen effects on the seminal vesicles, reduced plasma testosterone concentrations in intact males, and inhibited Ki67 expression. MK-4541 treated xenografts appeared similar to xenografts in castrated mice. Importantly, we demonstrate that MK-4541 exhibited anabolic activity in androgen deficient conditions, increasing lean body mass and muscle function in adult castrated mice. Moreover, MK-4541 treatment restored general activity levels in castrated mice. Thus, MK-4541 exhibits an optimum profile as an adjuvant therapy to ADT

  7. Exercise improves quality of life in androgen deprivation therapy-treated prostate cancer: systematic review of randomised controlled trials.

    Science.gov (United States)

    Teleni, Laisa; Chan, Raymond J; Chan, Alexandre; Isenring, Elisabeth A; Vela, Ian; Inder, Warrick J; McCarthy, Alexandra L

    2016-02-01

    Men receiving androgen deprivation therapy (ADT) for prostate cancer (PCa) are likely to develop metabolic conditions such as diabetes, cardiovascular disease, abdominal obesity and osteoporosis. Other treatment-related side effects adversely influence quality of life (QoL) including vasomotor distress, depression, anxiety, mood swings, poor sleep quality and compromised sexual function. The objective of this study was to systematically review the nature and effects of dietary and exercise interventions on QoL, androgen deprivation symptoms and metabolic risk factors in men with PCa undergoing ADT. An electronic search of CINAHL, CENTRAL, Medline, PsychINFO and reference lists was performed to identify peer-reviewed articles published between January 2004 and December 2014 in English. Eligible study designs included randomised controlled trials (RCTs) with pre- and post-intervention data. Data extraction and assessment of methodological quality with the Cochrane approach was conducted by two independent reviewers. Seven exercise studies were identified. Exercise significantly improved QoL, but showed no effect on metabolic risk factors (weight, waist circumference, lean or fat mass, blood pressure and lipid profile). Two dietary studies were identified, both of which tested soy supplements. Soy supplementation did not improve any outcomes. No dietary counselling studies were identified. No studies evaluated androgen-deficiency symptoms (libido, erectile function, sleep quality, mood swings, depression, anxiety and bone mineral density). Evidence from RCTs indicates that exercise enhances health- and disease-specific QoL in men with PCa undergoing ADT. Further studies are required to evaluate the effect of exercise and dietary interventions on QoL, androgen deprivation symptoms and metabolic risk factors in this cohort. © 2016 Society for Endocrinology.

  8. Involvement of different mechanisms for the association of CAG repeat length polymorphism in androgen receptor gene with prostate cancer

    Science.gov (United States)

    Mao, Xueying; Li, Jie; Xu, Xingxing; Boyd, Lara K; He, Weiyang; Stankiewicz, Elzbieta; Kudahetti, Sakunthala C; Cao, Guangwen; Berney, Daniel; Ren, Guosheng; Gou, Xin; Zhang, Hongwei; Lu, Yong-Jie

    2014-01-01

    While androgen and androgen receptor (AR) activity have been strongly implicated in prostate cancer development and therapy, the influence of the CAG repeat, which is found within the first exon of the AR gene, on prostate carcinogenesis is still unclear. We investigated the differences in the length of the CAG repeat between prostate cancer patients and controls in the Chinese population as well as between TMPRSS2:ERG fusion positive and negative samples. A general association between prostate cancer and either longer or shorter AR CAG repeat length was not observed in the Chinese population. However, our data suggest that certain CAG repeat lengths may increase or decrease prostate cancer risk. Shorter CAG repeat length was also not shown to be associated with a higher induction rate of TMPRSS2 and ERG proximity, an essential step for TMPRSS2:ERG fusion formation. However, samples with a CAG repeat of 17 were found more frequently in the TMPRSS2:ERG fusion positive than negative prostate cancer cases and mediated a higher rate of androgen-induced TMPRSS2 and ERG co-localisation than AR with longer (24) and shorter (15) CAG repeats. This suggests that 17 CAG repeats may be associated with TMPRSS2:ERG fusion positive prostate cancer, but may have a preventive role for prostate cancer in the Chinese population, which has a low TMPRSS2:ERG fusion frequency. This study suggests that different mechanisms for the association of CAG repeat length polymorphism and prostate cancer exist in different ethnic populations. PMID:25520876

  9. Androgen-Sensitized Apoptosis of HPr-1AR Human Prostate Epithelial Cells.

    Directory of Open Access Journals (Sweden)

    Congcong Chen

    Full Text Available Androgen receptor (AR signaling is crucial to the development and homeostasis of the prostate gland, and its dysregulation mediates common prostate pathologies. The mechanisms whereby AR regulates growth suppression and differentiation of luminal epithelial cells in the prostate gland and proliferation of malignant versions of these cells have been investigated in human and rodent adult prostate. However, the cellular stress response of human prostate epithelial cells is not well understood, though it is central to prostate health and pathology. Here, we report that androgen sensitizes HPr-1AR and RWPE-AR human prostate epithelial cells to cell stress agents and apoptotic cell death. Although 5α-dihydrotestosterone (DHT treatment alone did not induce cell death, co-treatment of HPr-1AR cells with DHT and an apoptosis inducer, such as staurosporine (STS, TNFt, or hydrogen peroxide, synergistically increased cell death in comparison to treatment with each apoptosis inducer by itself. We found that the synergy between DHT and apoptosis inducer led to activation of the intrinsic/mitochondrial apoptotic pathway, which is supported by robust cleavage activation of caspase-9 and caspase-3. Further, the dramatic depolarization of the mitochondrial membrane potential that we observed upon co-treatment with DHT and STS is consistent with increased mitochondrial outer membrane permeabilization (MOMP in the pro-apoptotic mechanism. Interestingly, the synergy between DHT and apoptosis inducer was abolished by AR antagonists and inhibitors of transcription and protein synthesis, suggesting that AR mediates pro-apoptotic synergy through transcriptional regulation of MOMP genes. Expression analysis revealed that pro-apoptotic genes (BCL2L11/BIM and AIFM2 were DHT-induced, whereas pro-survival genes (BCL2L1/BCL-XL and MCL1 were DHT-repressed. Hence, we propose that the net effect of these AR-mediated expression changes shifts the balance of BCL2-family proteins

  10. Early versus deferred androgen suppression therapy for patients with lymph node-positive prostate cancer after local therapy with curative intent: a systematic review

    Science.gov (United States)

    2013-01-01

    Background There is currently no consensus regarding the optimal timing for androgen suppression therapy in patients with prostate cancer that have undergone local therapy with curative intent but are proven to have node-positive disease without signs of distant metastases at the time of local therapy. The objective of this systematic review was to determine the benefits and harms of early (at the time of local therapy) versus deferred (at the time of clinical disease progression) androgen suppression therapy for patients with node-positive prostate cancer after local therapy. Methods The protocol was registered prospectively (CRD42011001221; http://www.crd.york.ac.uk/PROSPERO). We searched the MEDLINE, EMBASE, and CENTRAL databases, as well as reference lists, the abstracts of three major conferences, and three trial registers, to identify randomized controlled trials (search update 04/08/2012). Two authors independently screened the identified articles, assessed trial quality, and extracted data. Results Four studies including 398 patients were identified for inclusion. Early androgen suppression therapy lead to a significant decrease in overall mortality (HR 0.62, 95% CI 0.46-0.84), cancer-specific mortality (HR 0.34, 95% CI 0.18-0.64), and clinical progression at 3 or 9 years (RR 0.29, 95% CI 0.16-0.52 at 3 years and RR 0.49, 95% CI 0.36-0.67 at 9 years). One study showed an increase of adverse effects with early androgen suppression therapy. All trials had substantial methodological limitations. Conclusions The data available suggest an improvement in survival and delayed disease progression but increased adverse events for patients with node-positive prostate cancer after local therapy treated with early androgen suppression therapy versus deferred androgen suppression therapy. However, quality of data is low. Randomized controlled trials with blinding of outcome assessment, planned to determine the timing of androgen suppression therapy in node

  11. 5alphaDH-DOC (5alpha-dihydro-deoxycorticosterone) activates androgen receptor in castration-resistant prostate cancer.

    Science.gov (United States)

    Uemura, Motohide; Honma, Seijiro; Chung, Suyoun; Takata, Ryo; Furihata, Mutsuo; Nishimura, Kazuo; Nonomura, Norio; Nasu, Yasutomo; Miki, Tsuneharu; Shuin, Taro; Fujioka, Tomoaki; Okuyama, Akihiko; Nakamura, Yusuke; Nakagawa, Hidewaki

    2010-08-01

    Prostate cancer often relapses during androgen-depletion therapy, even under the castration condition in which circulating androgens are drastically reduced. High expressions of androgen receptor (AR) and genes involved in androgen metabolism indicate a continued role for AR in castration-resistant prostate cancers (CRPCs). There is increasing evidence that some amounts of 5alpha-dihydrotestosterone (DHT) and other androgens are present sufficiently to activate AR within CRPC tissues, and enzymes involved in the androgen and steroid metabolism, such as 5alpha-steroid reductases, are activated in CRPCs. In this report, we screened eight natural 5alphaDH-steroids to search for novel products of 5alpha-steroid reductases, and identified 11-deoxycorticosterone (DOC) as a novel substrate for 5alpha-steroid reductases in CRPCs. 11-Deoxycorticosterone (DOC) and 5alpha-dihydro-deoxycorticosterone (5alphaDH-DOC) could promote prostate cancer cell proliferation through AR activation, and type 1 5alpha-steroid reductase (SRD5A1) could convert from DOC to 5alphaDH-DOC. Sensitive liquid chromatography-tandem mass spectrometric analysis detected 5alphaDH-DOC in some clinical CRPC tissues. These findings implicated that under an extremely low level of DHT, 5alphaDH-DOC and other products of 5alpha-steroid reductases within CRPC tissues might activate the AR pathway for prostate cancer cell proliferation and survival under castration.

  12. Role of autonomous androgen receptor signaling in prostate cancer initiation is dichotomous and depends on the oncogenic signal.

    Science.gov (United States)

    Memarzadeh, Sanaz; Cai, Houjian; Janzen, Deanna M; Xin, Li; Lukacs, Rita; Riedinger, Mireille; Zong, Yang; DeGendt, Karel; Verhoeven, Guido; Huang, Jiaoti; Witte, Owen N

    2011-05-10

    The steroid hormone signaling axis is thought to play a central role in initiation and progression of many hormonally regulated epithelial tumors. It is unclear whether all cancer-initiating signals depend on an intact hormone receptor signaling machinery. To ascertain whether cell autonomous androgen receptor (AR) is essential for initiation of prostate intraepithelial neoplasia (PIN), the response of AR-null prostate epithelia to paracrine and cell autonomous oncogenic signals was assessed in vivo by using the prostate regeneration model system. Epithelial-specific loss of AR blocked paracrine FGF10-induced PIN, whereas the add back of exogenous AR restored this response. In contrast, PIN initiated by cell-autonomous, chronic-activated AKT developed independent of epithelial AR signaling. Our findings demonstrate a selective role for AR in the initiation of PIN, dependent on the signaling pathways driving tumor formation. Insights into the role of hormone receptor signaling in the initiation of epithelial tumors may help define this axis as a target for chemoprevention of carcinomas.

  13. Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant

    Science.gov (United States)

    Sun, Shihua; Sprenger, Cynthia C.T.; Vessella, Robert L.; Haugk, Kathleen; Soriano, Kathryn; Mostaghel, Elahe A.; Page, Stephanie T.; Coleman, Ilsa M.; Nguyen, Holly M.; Sun, Huiying; Nelson, Peter S.; Plymate, Stephen R.

    2010-01-01

    Progression of prostate cancer following castration is associated with increased androgen receptor (AR) expression and signaling despite AR blockade. Recent studies suggest that these activities are due to the generation of constitutively active AR splice variants, but the mechanisms by which these splice variants could mediate such effects are not fully understood. Here we have identified what we believe to be a novel human AR splice variant in which exons 5, 6, and 7 are deleted (ARv567es) and demonstrated that this variant can contribute to cancer progression in human prostate cancer xenograft models in mice following castration. We determined that, in human prostate cancer cell lines, ARv567es functioned as a constitutively active receptor, increased expression of full-length AR (ARfl), and enhanced the transcriptional activity of AR. In human xenografts, human prostate cancer cells transfected with ARv567es cDNA formed tumors that were resistant to castration. Furthermore, the ratio of ARv567es to ARfl expression within the xenografts positively correlated with resistance to castration. Importantly, we also detected ARv567es frequently in human prostate cancer metastases. In summary, these data indicate that constitutively active AR splice variants can contribute to the development of castration-resistant prostate cancers and may serve as biomarkers for patients who are likely to suffer from early recurrence and are candidates for therapies directly targeting the AR rather than ligand. PMID:20644256

  14. Prostate Carcinogenesis with Diabetes and Androgen-Deprivation-Therapy-Related Diabetes: An Update

    Directory of Open Access Journals (Sweden)

    Noboru Hara

    2012-01-01

    Full Text Available Prostate cancer and the androgen deprivation therapy (ADT thereof are involved in diabetes in terms of diabetes-associated carcinogenesis and ADT-related metabolic disorder, respectively. The aim of this study is to systematically review relevant literature. About 218,000 men are estimated to be newly diagnosed with prostate cancer every year in the United States. Approximately 10% of them are still found with metastasis, and in addition to them, about 30% of patients with nonmetastatic prostate cancer recently experience ADT. Population-based studies have shown that dissimilar to other malignancies, type 2 diabetes is associated with a lower incidence of prostate cancer, whereas recent large cohort studies have reported the association of diabetes with advanced high-grade prostate cancer. Although the reason for the lower prevalence of prostate cancer among diabetic men remains unknown, the lower serum testosterone and PSA levels in them can account for the increased risk of advanced disease at diagnosis. Meanwhile, insulin resistance already appears in 25–60% of the patients 3 months after the introduction of ADT, and long-term ADT leads to a higher incidence of diabetes (reported hazard ratio of 1.28–1.44. Although the possible relevance of cytokines such as Il-6 and TNF-α to ADT-related diabetes has been suggested, its mechanism is poorly understood.

  15. Does the Androgen Receptor (AR)-Regulated Map Kinase Phosphatase 1 (MKP-1) Enhance Castration-Resistant Prostate Cancer Survival under Therapeutic Stress?

    Science.gov (United States)

    2016-03-01

    in breast cancer models, and is inversely associated with apoptosis in preclinical prostate cancer models. Androgen and glucocorticoid signaling can... effects of both hormonal and chemotherapies. To date, significant progress has been made including optimization of MKP-1 protein detection...with apoptosis in preclinical prostate cancer models. Androgen and glucocorticoid signaling can induce MKP-1 expression; as mCRPC remains driven by

  16. Src promotes castration-recurrent prostate cancer through androgen receptor-dependent canonical and non-canonical transcriptional signatures.

    Science.gov (United States)

    Chattopadhyay, Indranil; Wang, Jianmin; Qin, Maochun; Gao, Lingqiu; Holtz, Renae; Vessella, Robert L; Leach, Robert W; Gelman, Irwin H

    2017-02-07

    Progression of prostate cancer (PC) to castration-recurrent growth (CRPC) remains dependent on sustained expression and transcriptional activity of the androgen receptor (AR). A major mechanism contributing to CRPC progression is through the direct phosphorylation and activation of AR by Src-family (SFK) and ACK1 tyrosine kinases. However, the AR-dependent transcriptional networks activated by Src during CRPC progression have not been elucidated. Here, we show that activated Src (Src527F) induces androgen-independent growth in human LNCaP cells, concomitant with its ability to induce proliferation/survival genes normally induced by dihydrotestosterone (DHT) in androgen-dependent LNCaP and VCaP cells. Src induces additional gene signatures unique to CRPC cell lines, LNCaP-C4-2 and CWR22Rv1, and to CRPC LuCaP35.1 xenografts. By comparing the Src-induced AR-cistrome and/or transcriptome in LNCaP to those in CRPC and LuCaP35.1 tumors, we identified an 11-gene Src-regulated CRPC signature consisting of AR-dependent, AR binding site (ARBS)-associated genes whose expression is altered by DHT in LNCaP[Src527F] but not in LNCaP cells. The differential expression of a subset (DPP4, BCAT1, CNTNAP4, CDH3) correlates with earlier PC metastasis onset and poorer survival, with the expression of BCAT1 required for Src-induced androgen-independent proliferation. Lastly, Src enhances AR binding to non-canonical ARBS enriched for FOXO1, TOP2B and ZNF217 binding motifs; cooperative AR/TOP2B binding to a non-canonical ARBS was both Src- and DHT-sensitive and correlated with increased levels of Src-induced phosphotyrosyl-TOP2B. These data suggest that CRPC progression is facilitated via Src-induced sensitization of AR to intracrine androgen levels, resulting in the engagement of canonical and non-canonical ARBS-dependent gene signatures.

  17. A small molecule polyamine oxidase inhibitor blocks androgen-induced oxidative stress and delays prostate cancer progression in the transgenic adenocarcinoma of the mouse prostate model.

    Science.gov (United States)

    Basu, Hirak S; Thompson, Todd A; Church, Dawn R; Clower, Cynthia C; Mehraein-Ghomi, Farideh; Amlong, Corey A; Martin, Christopher T; Woster, Patrick M; Lindstrom, Mary J; Wilding, George

    2009-10-01

    High levels of reactive oxygen species (ROS) present in human prostate epithelia are an important etiologic factor in prostate cancer (CaP) occurrence, recurrence, and progression. Androgen induces ROS production in the prostate by a yet unknown mechanism. Here, to the best of our knowledge, we report for the first time that androgen induces an overexpression of spermidine/spermine N1-acetyltransferase, the rate-limiting enzyme in the polyamine oxidation pathway. As prostatic epithelia produce a large excess of polyamines, the androgen-induced polyamine oxidation that produces H2O2 could be a major reason for the high ROS levels in the prostate epithelia. A small molecule polyamine oxidase inhibitor N,N'-butanedienyl butanediamine (MDL 72,527 or CPC-200) effectively blocks androgen-induced ROS production in human CaP cells, as well as significantly delays CaP progression and death in animals developing spontaneous CaP. These data show that polyamine oxidation is not only a major pathway for ROS production in prostate, but inhibiting this pathway also successfully delays CaP progression.

  18. Androgen-deprivation therapy-induced aggressive prostate cancer with neuroendocrine differentiation

    Directory of Open Access Journals (Sweden)

    Julia Lipianskaya

    2014-08-01

    Full Text Available Most prostate cancers (PCas are classified as acinar type (conventional adenocarcinoma which are composed of tumor cells with luminal differentiation including the expression of androgen receptor (AR and prostate-specific antigen (PSA. There are also scattered neuroendocrine (NE cells in every case of adenocarcinoma. The NE cells are quiesecent, do not express AR or PSA, and their function remains unclear. We have demonstrated that IL8-CXCR2-P53 pathway provides a growth-inhibitory signal and keeps the NE cells in benign prostate and adenocarcinoma quiescent. Interestingly, some patients with a history of adenocarcinoma recur with small cell neuroendocrine carcinoma (SCNC after hormonal therapy, and such tumors are composed of pure NE cells that are highly proliferative and aggressive, due to P53 mutation and inactivation of the IL8-CXCR2-P53 pathway. The incidence of SCNC will likely increase due to the widespread use of novel drugs that further inhibit AR function or intratumoral androgen synthesis. A phase II trial has demonstrated that platinum-based chemotherapy may be useful for such therapy-induced tumors.

  19. Molecular insight into the differential anti-androgenic activity of resveratrol and its natural analogs: In Silico approach to understand biological actions

    Science.gov (United States)

    The androgen receptor (AR) is a therapeutic target for the treatment of prostate cancer. Androgen receptor reactivation during the androgen-independent stage of prostate cancer is mediated by numerous mechanisms including expression of AR mutants and splice variants that become non-responsive to con...

  20. An Update on the Changing Indications for Androgen Deprivation Therapy for Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Kristene Myklak

    2011-01-01

    Full Text Available Quality of life has become increasingly more important for men diagnosed with prostate cancer. In light of this and the recognized risks of androgen deprivation therapy (ADT, the guidelines and use of ADT have changed significantly over the last few years. This paper reviews the current recommendations and the future perspectives regarding ADT. The benefits of ADT are evident neoadjuvantly and adjuvantly in patients treated with external beam radiation therapy for intermediate- and high-risk disease, in patients who have undergone prostatectomy with lymph node involvement, in high-risk patients after definitive therapy, and in patients who have developed progression or metastasis. Finally, this paper reviews the risks and benefits of each of these scenarios and the risks of androgen deprivation in general, and it delineates the areas where ADT was previously recommended, but where evidence is lacking for its additional benefit.

  1. A novel selective androgen receptor modulator, NEP28, is efficacious in muscle and brain without serious side effects on prostate.

    Science.gov (United States)

    Akita, Kazumasa; Harada, Koichiro; Ichihara, Junji; Takata, Naoko; Takahashi, Yasuhiko; Saito, Koichi

    2013-11-15

    Age-related androgen depletion is known to be a risk factor for various diseases, such as osteoporosis and sarcopenia. Furthermore, recent studies have demonstrated that age-related androgen depletion results in accumulation of β-amyloid protein and thereby acts as a risk factor for the development of Alzheimer's disease. Supplemental androgen therapy has been shown to be efficacious in treating osteoporosis and sarcopenia. In addition, studies in animals have demonstrated that androgens can play a protective role against Alzheimer's disease. However, androgen therapy is not used routinely for these indications, because of side effects. Selective androgen receptor modulators (SARMs) are a new class of compounds. SARMs maintain the beneficial effects of androgens on bone and muscle while reducing unwanted side effects. NEP28 is a new SARM exhibiting high selectivity for androgen receptor. To investigate the pharmacological effects of NEP28, we compared the effects on muscle, prostate, and brain with mice that were androgen depleted by orchidectomy and then treated with either placebo, NEP28, dihydrotestosterone, or methyltestosterone. We demonstrated that NEP28 showed tissue-selective effect equivalent to or higher than existing SARMs. In addition, the administration of NEP28 increased the activity of neprilysin, a known Aβ-degrading enzyme. These results indicate that SARM is efficacious for the treatment of not only osteoporosis and sarcopenia, but also Alzheimer's disease. © 2013 Published by Elsevier B.V.

  2. Integrating diet and exercise into care of prostate cancer patients on androgen deprivation therapy

    Directory of Open Access Journals (Sweden)

    Moyad MA

    2016-08-01

    Full Text Available Mark A Moyad,1 Robert U Newton,2 Ulf W Tunn,3 Damian Gruca4 1Department of Urology, University of Michigan Medical Center, Ann Arbor, MI, USA; 2Exercise Medicine Research Institute, Edith Cowan University, Joondalup, WA, Australia; 3Urological Clinic, Facharztzentrum Academic Hospital Sana Klinikum Offenbach, Offenbach/Main, 4Global Medical Affairs, AbbVie Deutschland, Ludwigshafen, Germany Abstract: Improved diagnosis and treatment regimens have resulted in greater longevity for men with prostate cancer. This has led to an increase in both androgen deprivation therapy (ADT use and duration of exposure, and therefore to its associated adverse effects, such as sexual dysfunction, osteoporosis, reduced muscle mass, increased fat mass, and increased incidence of cardiovascular disease and type 2 diabetes. Given that the adverse effects of ADT are systemic, often debilitating, and difficult to treat, efforts continue in the development of new strategies for long-term management of prostate cancer. The PubMed database was searched to select trials, reviews, and meta-analyses in English using such search terms as “prostate cancer” and “androgen deprivation therapy”, “cardiovascular risk”, “lean body mass”, “exercise”, and “diet”. The initial searches produced 379 articles with dates 2005 or more recent. Articles published after 2004 were favored. This review utilizes the latest data to provide a status update on the effects of exercise and diet on patients with prostate cancer, focusing on ADT-associated side effects, and it discusses the evidence for such interventions. Since the evidence of large-scale trials in patients with prostate cancer is missing, and an extrapolation of supporting data to all patient subgroups cannot be provided, individualized risk assessments remain necessary before the initiation of exercise and diet programs. Exercise, diet, and nutritional supplementation interventions have the potential to

  3. The metabolic syndrome and its components in patients with prostate cancer on androgen deprivation therapy.

    Science.gov (United States)

    Morote, Juan; Gómez-Caamaño, Antonio; Alvarez-Ossorio, José L; Pesqueira, Daniel; Tabernero, Angel; Gómez Veiga, Francisco; Lorente, José A; Porras, Mariano; Lobato, Juan J; Ribal, María J; Planas, Jacques

    2015-06-01

    Androgen deprivation therapy may promote the development of the metabolic syndrome in patients with prostate cancer. We assessed the prevalence of the full metabolic syndrome and its components during the first year of androgen deprivation therapy. This observational, multicenter, prospective study included 539 patients with prostate cancer scheduled to receive 3-month depot luteinizing hormone-releasing hormone analogs for more than 12 months. Waist circumference, body mass index, lipid profile, blood pressure and fasting glucose were evaluated at baseline and after 6 and 12 months. The metabolic syndrome was assessed according to NCEP ATP III criteria (2001) and 4 other definitions (WHO 1998, AACE 2003, AHA/NHLBI 2005 and IDF 2005). At 6 and 12 months after the initiation of androgen deprivation therapy, significant increases were observed in waist circumference, body mass index, fasting glucose, triglycerides, total cholesterol, and high-density and low-density lipoprotein cholesterol. No significant changes in blood pressure 130/85 or greater were detected. A nonsignificant increase of 3.9% in the prevalence of the full metabolic syndrome (ATP III) was observed (22.9% at baseline vs 25.5% and 26.8% at 6 and 12 months, respectively). The prevalence of the metabolic syndrome at baseline varied according to the definition used, ranging from 9.4% (WHO) to 50% (IDF). At 12 months significant increases in prevalence were observed with the WHO (4.1%) and AHA/NHLBI (8.1%) definitions. Androgen deprivation therapy produces significant early effects on waist circumference, body mass index, fasting glucose, triglycerides and cholesterol. The prevalence of and increase in the metabolic syndrome depend on the defining criteria. Counseling patients on the prevention, early detection and treatment of specific metabolic alterations is recommended. Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  4. Proteomic interrogation of androgen action in prostate cancer cells reveals roles of aminoacyl tRNA synthetases.

    Directory of Open Access Journals (Sweden)

    Adaikkalam Vellaichamy

    2009-09-01

    Full Text Available Prostate cancer remains the most common malignancy among men in United States, and there is no remedy currently available for the advanced stage hormone-refractory cancer. This is partly due to the incomplete understanding of androgen-regulated proteins and their encoded functions. Whole-cell proteomes of androgen-starved and androgen-treated LNCaP cells were analyzed by semi-quantitative MudPIT ESI- ion trap MS/MS and quantitative iTRAQ MALDI- TOF MS/MS platforms, with identification of more than 1300 high-confidence proteins. An enrichment-based pathway mapping of the androgen-regulated proteomic data sets revealed a significant dysregulation of aminoacyl tRNA synthetases, indicating an increase in protein biosynthesis- a hallmark during prostate cancer progression. This observation is supported by immunoblot and transcript data from LNCaP cells, and prostate cancer tissue. Thus, data derived from multiple proteomics platforms and transcript data coupled with informatics analysis provides a deeper insight into the functional consequences of androgen action in prostate cancer.

  5. Preferred treatment frequency in patients receiving androgen deprivation therapy for advanced prostate cancer

    DEFF Research Database (Denmark)

    Fode, Mikkel; Nielsen, Torben K; Al-Hamadani, Muhammad

    2014-01-01

    OBJECTIVE: The aim of this study was to assess patient preference regarding the length of treatment intervals of androgen deprivation therapy (ADT) with gonadotropin-releasing hormone agonists for prostate cancer. MATERIAL AND METHODS: The study was conducted as a questionnaire-based, cross...... the pressure on healthcare systems and may be of benefit for a large group of patients. However, it cannot be prescribed blindly without possibly affecting patient satisfaction. The choice of treatment intervals should be made in collaboration between the physician and the patient....

  6. Interaction Between a Novel p21 Activated Kinase (PAK6) and Androgen Receptor in Prostate Cancer

    Science.gov (United States)

    2005-02-01

    of LNCaP of LY294002 from 25-100 MM, the expression of PSA was sig - cells with LY294002 results in a decreased level of expression nificantly reduced...P13K and androgen signaling. A model summarizes PI3KIAkt sig - clear levels of j-catenin. Consequently, increased f-catenin naling in prostate cells...Arvelaiz Y, Thompson TC, Sepulveda JL, Chinault AC. LAPSERI: a novel 1997;57:495-9. candidate tumor suppressor gene from 10q2 4.3. Oncogene 2001;20:6707

  7. Anti-androgenic effects of S-40542, a novel non-steroidal selective androgen receptor modulator (SARM) for the treatment of benign prostatic hyperplasia.

    Science.gov (United States)

    Nejishima, Hiroaki; Yamamoto, Noriko; Suzuki, Mika; Furuya, Kazuyuki; Nagata, Naoya; Yamada, Shizuo

    2012-10-01

    Selective androgen receptor modulators (SARMs) would provide alternative therapeutic agent for androgen-related diseases. We identified a tetrahydroquinoline (THQ) derivative, 1-(8-nitro-3a, 4, 5, 9b-tetrahydro-3H-cyclopenta[c]quinolin-4-yl) ethane-1, 2-diol (S-40542) as a novel SARM antagonist. Affinity for nuclear receptors of S-40542 was evaluated in receptor-binding studies. Androgen receptor (AR) transcriptional activity of S-40542 was investigated by luciferase reporter assay in DU145AR cells. Normal and benign prostatic hyperplasia (BPH) model rats were repeatedly treated with S-40542 and flutamide. The tissue weights of prostate and levator ani muscle as well as blood levels of testosterone and luteinizing hormone were measured. S-40542 bound to the AR with high affinity. S-40542 at relatively high concentrations increased the transcriptional activity. This agent also showed a concentration-dependent AR antagonistic action in the presence of 1 nM 5α-dihydrotestosterone. Repeated treatment with S-40542 and flutamide decreased dose-dependently the weights of the prostate to a similar extent. In contrast, the tissue weight-reducing effect by S-40542 treatment on the levator ani muscle was much weaker than that of flutamide. S-40542 had little effect on the blood level of testosterone and luteinizing hormone, whereas flutamide increased the level of both hormones. Furthermore, S-40542 decreased dose-dependently prostate weight of BPH rats. The current results indicate that S-40542 possesses the prostate-selective SARM activity, suggestive of clinical benefit against benign prostate hyperplasia. THQ compounds may be useful for the research of mode of action of SARMs and for the development of safe SARM antagonists. Copyright © 2012 Wiley Periodicals, Inc.

  8. Androgen receptor variant-7: an important predictive biomarker in castrate resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    Oliver Sartor

    2015-06-01

    Full Text Available The recent manuscript in New England Journal of Medicine by Antonarakis et al. [1] has important clinical implications. This study evaluates mRNA expression of a particular androgen receptor splice variant-7 (AR-V7, in circulating tumor cells (CTCs from metastatic castrate-resistant prostate cancer (mCRPC patients receiving enzalutamide or abiraterone. The findings were striking, none of the 18 patients with detectable AR-V7 in CTCs had prostate-specific antigen (PSA responses. Further, the median time to PSA progression after enzalutamide or abiraterone treatment was only 1.3-1.4 months in AR-V7-positive patients as compared to 5.3-6.1 months in AR-V7 negative patients. AR-V7 in CTCs was also associated with shorter survival.

  9. Gene expression changes in rat prostate after activation or blocking of the androgen and estrogen receptor

    DEFF Research Database (Denmark)

    Nellemann, Christine Lydia; Dalgaard, Majken; Holst, Bjørn

    2005-01-01

    responsive genes (complement C3, ER alpha, ER beta, AR, TRPM-2, PBPC3, ODC, and IGF-1 mRNA) was analyzed in rat ventral prostate by real time RT-PCR. Administration of estradiol benzoate (EB) to castrated testosterone-treated rats had no effect on reproductive organ weights or gene expression levels...... and the anti-estrogen, ICI 182780, only affected ODC expression. Therefore, estrogenic or anti-estrogenic compounds would not be expected to seriously affect the outcome of a Hershberger test. However, EB given alone to castrated rats resulted in various effects. EB increased seminal vesicle weight, an effect....... These data indicate that estrogens have various effects in castrated male rats and that expression of several genes is under multi-hormonal control in the ventral prostate. However, interactions between estrogens and androgens do not play a major role in the Hershberger assay, as simultaneous TP...

  10. The prostate after administration of anabolic androgenic steroids: a morphometrical study in rats.

    Science.gov (United States)

    Vargas, Rafael Arêas; Oliveira, Leonardo Pires; Frankenfeld, Stephan; Souza, Diogo Benchimol de; Costa, Waldemar Silva; Favorito, Luciano Alves; Sampaio, Francisco José Barcellos

    2013-01-01

    Many adverse effects have been associated with abuse of anabolic-androgenic steroids (AAS), including disorders of the urogenital tract. The objective of this study is to analyze the morphological modifications in the prostate ventral lobe of pubertal and adult rats chronically treated with AAS, using morphometric methods. We studied 39 male Wistar rats weighing between 400 g and 550 g. The rats were divided into four groups: (a) control rats, with 105 days of age (C105) (n = 7); (b) control rats with 65 days of age (C65) (n = 9), injected only with the vehicle (peanut oil); (c) treated rats, with 105 days of age (T105) (n = 10) and (d) treated rats with 65 days of age (T65) (n = 13). The treated rats were injected with nandrolone decanoate at a dose of 10 mg.Kg-1 body weight. The steroid hormone and the vehicle were administered by intramuscular injection once a week for eight weeks. The rats were killed at 161 days of age (C105 and T105) and 121 days of age (C65 and T65) and the ventral prostate lobe was dissected and processed for histology. The height of the acinar epithelium, the surface densities of the lumen, epithelium and stroma were observed with X400 magnification using an Olympus light microscope coupled to a Sony CCD video camera, and the images transferred to a Sony monitor KX14-CP1. The selected histological areas were then quantified using the M42 test-grid system on the digitized fields. The data were analyzed with the Graphpad software. To compare the quantitative data in both groups (controls and treated) and the outcomes, Student's t-test was used (p anabolic androgenic steroids in rats promotes structural changes in the prostate. We observed structural changes in the weight, volume and epithelium height of the prostate ventral lobe and a predominance of collagen fibers.

  11. SLCO2B1 and SLCO1B3 as New Targets for Enhancing Androgen Deprivation Therapy for Prostate Cancer

    Science.gov (United States)

    2015-10-01

    Wang Y-K, Charng M-J, Ueng Y-F. Determination of serum atorvastatin concentrations in lipid-controlling patients with and without myalgia syndrome ...specific antigen levels: analysis of the National Health and Nutrition Examination Survey. Journal of clinical oncology : official journal of the...in prostate cancer. Curr Opin Oncol 24:251-7, 2012 6. Mostaghel EA, Nelson PS: Intracrine androgen metabolism in prostate cancer progression

  12. Development of a New Class of Drugs To Inhibit All Forms of Androgen Receptor in Castration Resistant Prostate Cancers

    Science.gov (United States)

    2016-10-01

    concentration of VPC-14449 suppressed the mitosis gene UBE2C, a known target of ARV7 (Hu et al., 2012, Cancer Res.). Fig. 6. PCa cell were cultured...Prostate Cancers PRINCIPAL INVESTIGATOR: Paul Rennie CONTRACTING ORGANIZATION: University of British Columbia Vancouver V6T 1Z3 REPORT DATE...All Forms of Androgen Receptor in Castration-Resistant Prostate Cancers 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT

  13. Clinical Usefulness of Chlormadinone Acetate as an Alternative Antiandrogen Therapy for Prostate Cancer Relapse after Combined Androgen Blockade Therapy

    OpenAIRE

    江原, 英俊; 加藤, 成一; 中根, 慶太; 加藤, 卓; 高田, 俊彦; 小島, 圭太郎; 亀井, 信吾; 萩原, 徳康; 柚原, 一哉; 高橋, 義人; 藤本, 佳則; 藤広, 茂; 蟹本, 雄右; 出口, 隆

    2009-01-01

    We prospectively studied the usefulness of chlormadinone acetate (CMA) as an alternative therapy for prostate cancer relapse after combined androgen blockade (CAB) therapy. Sixteen patients with relapsed prostate cancer after treatment with CAB, including surgical or medical castration and nonsteroidal antiandrogens, 80 mg bicalutamide daily or 375 mg flutamide daily, were enrolled. After discontinuing the antiandrogen for evaluating the patient for the antiandrogen withdrawal syndrome, we ad...

  14. Prognostic significance of genetic polymorphisms in disease progression and survival in prostate cancer after androgen deprivation therapy

    Directory of Open Access Journals (Sweden)

    Tsung-Yi Huang

    2015-06-01

    Full Text Available It is believed that androgens and their receptors regulate normal prostate growth and mediate prostate cancer development. Androgen deprivation therapy is the most commonly used treatment for advanced prostate cancer. Although the therapy is initially effective, progression of the disease to castration-resistant prostate cancer is almost inevitable, leading to treatment failure. Despite the existence of current clinical parameters, new biomarkers are urgently needed to improve the prognosis. Some molecules and DNA-based genetic biomarkers are under investigation as potential prognostic factors. The advancement in molecular cytogenetic research, such as genome-wide association for single-nucleotide polymorphisms, has made possible the detection of genetic mutations. In this study, a literature search from August 1985 to April 2013 was performed through the PubMed database using the keywords “genetic polymorphisms”, “prostate cancer” and “androgen deprivation therapy”. The results revealed that several genome-wide association studies (such as rs16901979, rs7931342, HSD17B4, rs6162 in the CYP17A1, rs4243229 and rs7201637 in the HSD17B2, rs1062577 in the ESR1, SLCO1B3, SLCO2B1, rs2939244 in the ARRDC3, rs9508016 in the FLT1, rs6504145 in the SKAP1, rs7830611 in the FBXO32, rs9508016 in the FLT1, rs12529 in the AKR1C3, rs16934641 in the BNC2, rs3763763 in the TACC2, rs2051778 in the ALPK1, and rs3763763 in the TACC2, AR, ESR1, and ESR2 and single-nucleotide polymorphisms in important pathways (such as androgen signal, biosynthesis, metabolism, androgen receptor binding site, response element, androgen receptor CAG repeat polymorphism length, and estrogen receptor-binding sites involved in prostate cancer occurrence and mechanism could serve as candidate biomarkers for the early detection of castration-resistant prostate cancer after androgen deprivation therapy. Additional investigations are required to decipher precisely the gene

  15. Tumor Restrictive Gene Therapy for Metastatic Prostate Cancer

    National Research Council Canada - National Science Library

    Gardner, Thomas

    2001-01-01

    ...) to specifically target and lyse cells of an androgen independent prostate cancer osseous metastasis, which account for a majority of the morbidity and mortality experience by men with prostate cancer...

  16. Tumor Restrictive Gene Therapy for Metastatic Prostate Cancer

    National Research Council Canada - National Science Library

    Gardner, Thomas

    2000-01-01

    ...) to specifically target and lyse cells of an androgen independent prostate cancer osseous metastasis, which account for a majority of the morbidity and mortality experience by men with prostate cancer...

  17. Androgen Induces Adaptation to Oxidative Stress in Prostate Cancer: Implications for Treatment with Radiation Therapy

    Directory of Open Access Journals (Sweden)

    Jehonathan H. Pinthus

    2007-01-01

    Full Text Available Radiation therapy is a standard treatment for prostate cancer (PC. The postulated mechanism of action for radiation therapy is the generation of reactive oxygen species (ROS. Adjuvant androgen deprivation (AD therapy has been shown to confer a survival advantage over radiation alone in high-risk localized PC. However, the mechanism of this interaction is unclear. We hypothesize that androgens modify the radioresponsiveness of PC through the regulation of cellular oxidative homeostasis. Using androgen receptor (AR+ 22rv1 and AR− PC3 human PC cell lines, we demonstrated that testosterone increased basal reactive oxygen species (bROS levels, resulting in dose-dependent activation of phospho-p38 and pAKT, increased expression of clusterin, catalase, manganese superoxide dismutase. Similar data were obtained in three human PC xenografts; WISH-PC14, WISH-PC23, CWR22, growing in testosterone-supplemented or castrated SCID mice. These effects were reversible through AD or through incubation with a reducing agent. Moreover, testosterone increased the activity of catalase, superoxide dismutases, glutathione reductase. Consequently, AD significantly facilitated the response of AR+ cells to oxidative stress challenge. Thus, testosterone induces a preset cellular adaptation to radiation through the generation of elevated bROS, which is modified by AD. These findings provide a rational for combined hormonal and radiation therapy for localized PC.

  18. Racial Variations in Prostate Cancer Molecular Subtypes and Androgen Receptor Signaling Reflect Anatomic Tumor Location.

    Science.gov (United States)

    Faisal, Farzana A; Sundi, Debasish; Tosoian, Jeffrey J; Choeurng, Voleak; Alshalalfa, Mohammed; Ross, Ashley E; Klein, Eric; Den, Robert; Dicker, Adam; Erho, Nicholas; Davicioni, Elai; Lotan, Tamara L; Schaeffer, Edward M

    2016-07-01

    Prostate cancer (PCa) subtypes based on ETS gene expression have been described. Recent studies suggest there are racial differences in tumor location, with PCa located anteriorly more often among African-American (AA) compared to Caucasian-American (CA) men. In this retrospective analysis of a multi-institutional cohort treated by radical prostatectomy (179 CA, 121 AA), we evaluated associations among molecular subtype, race, anatomic tumor location, and androgen receptor (AR) signaling. Subtype (m-ERG(+), m-ETS(+), m-SPINK1(+), or triple-negative) was determined using distribution-based outlier analysis. AR signaling was investigated using gene expression profiling of canonical AR targets. m-ERG(+) was more common in CA than AA men (47% vs 22%, pRacial differences in molecular subtypes did not persist when tumors were analyzed by location, suggesting a biologically important relationship between tumor location and subtype. Accordingly, anterior tumor location was associated with higher Decipher scores and lower global AR signaling. This study demonstrates associations among patient race, prostate cancer molecular subtypes, and tumor location. Location-specific differences in androgen regulation may further underlie these relationships. Copyright © 2015. Published by Elsevier B.V.

  19. Androgen Receptor Deregulation Drives Bromodomain-Mediated Chromatin Alterations in Prostate Cancer.

    Science.gov (United States)

    Urbanucci, Alfonso; Barfeld, Stefan J; Kytölä, Ville; Itkonen, Harri M; Coleman, Ilsa M; Vodák, Daniel; Sjöblom, Liisa; Sheng, Xia; Tolonen, Teemu; Minner, Sarah; Burdelski, Christoph; Kivinummi, Kati K; Kohvakka, Annika; Kregel, Steven; Takhar, Mandeep; Alshalalfa, Mohammed; Davicioni, Elai; Erho, Nicholas; Lloyd, Paul; Karnes, R Jeffrey; Ross, Ashley E; Schaeffer, Edward M; Vander Griend, Donald J; Knapp, Stefan; Corey, Eva; Feng, Felix Y; Nelson, Peter S; Saatcioglu, Fahri; Knudsen, Karen E; Tammela, Teuvo L J; Sauter, Guido; Schlomm, Thorsten; Nykter, Matti; Visakorpi, Tapio; Mills, Ian G

    2017-06-06

    Global changes in chromatin accessibility may drive cancer progression by reprogramming transcription factor (TF) binding. In addition, histone acetylation readers such as bromodomain-containing protein 4 (BRD4) have been shown to associate with these TFs and contribute to aggressive cancers including prostate cancer (PC). Here, we show that chromatin accessibility defines castration-resistant prostate cancer (CRPC). We show that the deregulation of androgen receptor (AR) expression is a driver of chromatin relaxation and that AR/androgen-regulated bromodomain-containing proteins (BRDs) mediate this effect. We also report that BRDs are overexpressed in CRPCs and that ATAD2 and BRD2 have prognostic value. Finally, we developed gene stratification signature (BROMO-10) for bromodomain response and PC prognostication, to inform current and future trials with drugs targeting these processes. Our findings provide a compelling rational for combination therapy targeting bromodomains in selected patients in which BRD-mediated TF binding is enhanced or modified as cancer progresses. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  20. Rising prostate-specific antigen values during neoadjuvant androgen deprivation therapy: The importance of monitoring

    International Nuclear Information System (INIS)

    Niblock, Paddy; Pickles, Tom

    2006-01-01

    Purpose: To assess the impact of a rising prostate-specific antigen (PSA) level in patients receiving neoadjuvant androgen deprivation therapy (N-ADT) before external beam radiotherapy for prostate cancer. Methods and Materials: From prospectively collected data, we identified 182 patients who received between 3 and 12 months of N-ADT before definitive external beam radiotherapy and who had at least three PSA readings during the neoadjuvant period. One hundred fifty patients had PSA values that continued to fall (Non-Rise group), but 32 had a PSA value that started to rise (Rise group). The two groups were compared by Mann-Whitney U and Pearson chi-square tests. Kaplan-Meier and log-rank analyses were performed for time to treatment failure, cause-specific survival (CSS), and overall survival (OS). Results: The median follow-up was 62.5 months for the Non-Rise group and 53 months for the Rise group. Patients who sustained a PSA rise during the N-ADT period had a shorter time to PSA relapse (p = 0.013), poorer CSS (p = 0.027), and poorer OS (p = 0.03). Multivariate analysis confirms the significance of a PSA rise during the N-ADT period for CSS (p = 0.035) and OS (p = 0.038). Conclusions:: A subset of patients treated with N-ADT develop a rising PSA profile that likely represents early androgen resistance. They have significantly worse outcome

  1. Androgen deprivation in prostate cancer and the long-term risk of fracture.

    Science.gov (United States)

    Ojeda, S; Lloret, M; Naranjo, A; Déniz, F; Chesa, N; Domínguez, C; Lara, P C

    2017-10-01

    To determine the rate of bone mass loss and the risk of fracture induced by androgen deprivation therapy in patients with prostate cancer. Prospective study in 2 phases. In the first phase, demographic variables, FRAX ® , bone mineral density and clinical fractures were collected, before starting the therapy and up to 1 year after ending the therapy. In the second phase, we conducted a telephone interview a mean of 8.5 years after the start of the study to assess new fractures. We included 150 patients with a mean age of 67 years and a mean therapy duration of 24 months. Before starting the treatment, 62 patients (41%) showed osteoporosis or low bone mass in the densitometry. After the first year of treatment, the bone mineral density decreased a mean of 3.7% and 2.1% in the lumbar spine and femoral neck, respectively. At the end of the second and third year, the loss rate was lower. During the first phase of the study, 4 patients (2.7%) experienced a fracture. In the telephone interviews with 80 patients (53%), only 1 had experienced a fracture. In the patients with prostate cancer and androgen deprivation therapy, greater bone loss occurred during the first year. When the treatment did not exceed 2 years, the absolute risk of fracture was low, and clinical fractures were uncommon in the short and long term. Copyright © 2017 AEU. Publicado por Elsevier España, S.L.U. All rights reserved.

  2. Regulation of human CYP27A1 by estrogens and androgens in HepG2 and prostate cells.

    Science.gov (United States)

    Tang, Wanjin; Norlin, Maria; Wikvall, Kjell

    2007-06-01

    The regulation of the human CYP27A1 gene by estrogens and androgens was studied in human liver-derived HepG2 and prostate cells. Our results show that the promoter activity, enzymatic activity and mRNA levels of CYP27A1 in HepG2 cells are downregulated by estrogen in presence of ERalpha or ERbeta. Similar effects by estrogen were found in RWPE-1 prostate cells. In contrast, estrogen markedly upregulated the transcriptional activity of CYP27A1 in LNCaP prostate cancer cells. 5alpha-Dihydrotestosterone and androgen receptor upregulated the transcriptional activity of CYP27A1 in HepG2 cells. Progressive deletion experiments indicate that the ERbeta-mediated effects in HepG2 and LNCaP cells are conferred to the same region (-451/+42) whereas ERalpha-mediated effects on this promoter are more complex. The results indicate that the stimulating effect of androgen in HepG2 cells is conferred to a region upstream from -792 in the CYP27A1 promoter. In summary, we have identified the human CYP27A1 gene as a target for estrogens and androgens. The results imply that expression of CYP27A1 may be affected by endogenous sex hormones and pharmacological compounds with estrogenic or androgenic effects.

  3. The Integrin-Regulated Kinase PYK-2: A Therapeutic Target for Prostate Cancer

    National Research Council Canada - National Science Library

    Edlund, Magnus

    2001-01-01

    ...) . A number of promising therapeutic targets for androgen-independent and metastatic prostate cancers are contained within the signaling cascades downstream of the ECM-binding Integrin molecules...

  4. Adjuvant androgen deprivation therapy augments cure and long-term cancer control in men with poor prognosis, nonmetastatic prostate cancer.

    NARCIS (Netherlands)

    Fleshner, N.; Keane, T.E.; Lawton, C.A.; Mulders, P.F.A.; Payne, H.; Taneja, S.S.; Morris, T.

    2008-01-01

    Historically, adjuvant androgen deprivation therapy has been viewed as a palliative treatment option for patients with poor-prognosis non-metastatic prostate cancer. In addition, guidelines from bodies such as the European Association of Urology and American Society for Clinical Oncology do not

  5. Hot flushes in prostatic cancer patients during androgen-deprivation therapy with monthly dose of degarelix or leuprolide

    DEFF Research Database (Denmark)

    Iversen, P; Karup, C; van der Meulen, E

    2011-01-01

    The aim of the study was to compare the onset, incidence and frequency/intensity of hot flushes during androgen-deprivation therapy with a gonadotropin-releasing hormone antagonist (GnRH) blocker versus an agonist using data from a randomized Phase 3 clinical trial. In total, 610 prostate cancer...

  6. Tissue polypeptide-specific antigen (TPS) determinations before and during intermittent maximal androgen blockade in patients with metastatic prostatic carcinoma

    NARCIS (Netherlands)

    Kil, P. J. M.; Goldschmidt, H. M. J.; Wieggers, B. J. A.; Kariakine, O. B.; Studer, U. E.; Whelan, P.; Hetherington, J.; de Reijke, Th M.; Hoekstra, J. W.; Collette, L.

    2003-01-01

    To evaluate the prognostic significance of serially measured tissue polypeptide-specific antigen (TPS) levels in patients with metastatic prostatic carcinoma treated with intermittent maximal androgen blockade (MAB). To determine its value with respect to predicting response to treatment and time to

  7. Parenteral estrogen versus combined androgen deprivation in the treatment of metastatic prostatic cancer: part 2. Final evaluation of the Scandinavian Prostatic Cancer Group (SPCG) Study No. 5

    DEFF Research Database (Denmark)

    Hedlund, P.O.; Damber, J.E.; Hagerman, I.

    2008-01-01

    To compare parenteral estrogen therapy in the form of high-dose polyestradiol phosphate (PEP; Estradurin) with combined androgen deprivation (CAD) in the treatment of prostate cancer patients with skeletal metastases. The aim of the study was to compare anticancer efficacy and adverse events...

  8. Androgenic Regulation of White Adipose Tissue-Prostate Cancer Interactions

    Science.gov (United States)

    2015-08-01

    Roberts, D.L., Dive, C., Renehan, A.G., 2010. Biological mechanisms linking obesity and cancer risk: new perspectives. Annu. Rev. Med. 61, 301–316...independent risk factor for the development of type 2 diabetes mellitus as well as myocardial infarction, stroke, and certain cancers (Galic et al., 2010...McWhirter, C.L., Mager, D.E., Ghanim, H., Chaudhuri, A., Dandona, P., 2010. Testosterone concentrations in diabetic and nondiabetic obese men. Diabetes

  9. Targeting Androgen Receptor and JunD Interaction for Prevention of Prostate Cancer Progression

    Science.gov (United States)

    Mehraein-Ghomi, Farideh; Kegel, Stacy J.; Church, Dawn R.; Schmidt, Joseph S.; Reuter, Quentin R.; Saphner, Elizabeth L.; Basu, Hirak S.; Wilding, George

    2014-01-01

    BACKGROUND Multiple studies show that reactive oxygen species (ROS) play a major role in prostate cancer (PCa) development and progression. Previously, we reported an induction of Spermidine/Spermine N1-Acetyl Transferase (SSAT) by androgen-activated androgen receptor (AR)-JunD protein complex that leads to over-production of ROS in PCa cells. In our current research, we identify small molecules that specifically block AR-JunD in this ROS-generating metabolic pathway. METHODS A high throughput assay based on Gaussia Luciferase reconstitution was used to identify inhibitors of the AR-JunD interaction. Selected hits were further screened using a fluorescence polarization competitor assay to eliminate those that bind to the AR Ligand Binding Domain (LBD), in order to identify molecules that specifically target events downstream to androgen activation of AR. Eleven molecules were selected for studies on their efficacy against ROS generation and growth of cultured human PCa cells by DCFH dye-oxidation assay and DNA fluorescence assay, respectively. In situ Proximity Ligation Assay (PLA), SSAT promoter-luciferase reporter assay, and western blotting of apoptosis and cell cycle markers were used to study mechanism of action of the lead compound. RESULTS Selected lead compound GWARJD10 with EC50 10 μM against ROS production was shown to block AR-JunD interaction in situ as well as block androgen-induced SSAT gene expression at IC50 5 μM. This compound had no effect on apoptosis markers, but reduced cyclin D1 protein level. CONCLUSIONS Inhibitor of AR-JunD interaction, GWARJD10 shows promise for prevention of progression of PCa at an early stage of the disease by blocking growth and ROS production. PMID:24647988

  10. The Rab27a-binding protein, JFC1, regulates androgen-dependent secretion of prostate-specific antigen and prostatic-specific acid phosphatase1

    OpenAIRE

    Johnson, Jennifer L.; Ellis, Beverly A.; Noack, Deborah; Seabra, Miguel C.; Catz, Sergio D.

    2005-01-01

    Two of the major proteins secreted by the prostate epithelium secretory cells are PSA (prostate-specific antigen) and PSAP (prostatic-specific acid phosphatase). The molecules involved in the secretory machinery of PSA and PSAP, and the regulation of this machinery, remain unknown. In the present paper, we provide evidence that JFC1 [synaptotagmin-like protein (slp1)], a Rab27a- and PtdIns(3,4,5)P3-binding protein, regulates the androgen-dependent secretion of PSAP and PSA in human LNCaP pros...

  11. Risk factors for bone loss with prostate cancer in Korean men not receiving androgen deprivation therapy

    Directory of Open Access Journals (Sweden)

    Sun-Ouck Kim

    2009-04-01

    Full Text Available PURPOSE: Preexisting bone loss in men with prostate cancer is an important issue due to the accelerated bone loss during androgen deprivation therapy (ADT. In addition, a high prostate-specific antigen (PSA level has been reported to be related to bone metabolism. This study assessed the factors associated with osteoporosis in Korean men with non-metastatic prostate cancer before undergoing ADT. MATERIAL AND METHODS: The study enrolled patients admitted for a prostate biopsy because of a high PSA or palpable nodule on a digital rectal examination. We divided the patients (n = 172 according to the results of the biopsy: group I, non-metastatic prostate cancer (n = 42 and group II, benign prostatic hypertrophy (BPH; n = 130. The lumbar bone mineral density (BMD was evaluated using quantitative computed tomography. The demographic, health status, lifestyle, body mass index (BMI, serum testosterone concentration, and disease variables in prostate cancer (Gleason score, clinical stage, and PSA were analyzed prospectively to determine their effect on the BMD. RESULTS: The estimated mean T-score was higher in group I than in group II (-1.96 ± 3.35 vs. -2.66 ± 3.20, but without statistic significance (p = 0.235. The significant factors correlated with BMD in group I were a high serum PSA (ß = -0.346, p = 0.010 and low BMI (ß = 0.345, p = 0.014 in the multiple linear regression model. Also old age (r = -0.481, p = 0.001, a high serum PSA (r = -0.571, p < 0.001, low BMI (r = 0.598, p < 0.001, and a high Gleason’s score (r = -0.319, p = 0.040 were the factors related to BMD in the correlation. The significant factors correlated with BMD in group II were old age (ß = -0.324, p = 0.001 and BMI (ß = 0.143, p = 0.014 in the multiple linear regression model. CONCLUSIONS: The risk factors for osteoporosis in men with prostate cancer include a low BMI, and elevated serum PSA. Monitoring BMD from the outset of ADT is a logical first step in the clinical

  12. PROGNOSTIC VALUE OF THE BASELINE VALUES OF SERUM TESTOSTERONE AND FREE ANDROGEN INDEX IN PATIENTS WITH PROSTATE CANCER

    Directory of Open Access Journals (Sweden)

    M. E. Grigoryev

    2012-01-01

    Full Text Available The growing incidence of prostate cancer (PC and its variable nature are an important problem today. PC is distinguished by its latent ability in many cases, which makes its screening difficult.Prostate-specific antigen (PSA is one of the most common tumor markers of PC, which are used for mass male screening. However, the detection rate of PC in men with normal PSA values is also very high. This promotes an active search for new markers and predictors of PC.The effect of androgens on hormonal carcinogenesis in the prostate suggests that the analysis of serum testosterone concentrations and free androgen index may be made in patients with low PSA levels in the early diagnosis and prognosis of PC.

  13. The AhR Ligand, TCDD, Regulates Androgen Receptor Activity Differently in Androgen-Sensitive versus Castration-Resistant Human Prostate Cancer Cells

    Directory of Open Access Journals (Sweden)

    Maryam Ghotbaddini

    2015-07-01

    Full Text Available The reported biological effects of TCDD include induction of drug metabolizing enzymes, wasting syndrome and tumor promotion. TCDD elicits most of its effects through binding the aryl hydrocarbon receptor (AhR. TCDD induced degradation of AhR has been widely reported and requires ubiquitination of the protein. The rapid depletion of AhR following TCDD activation serves as a mechanism to modulate AhR mediated gene induction. In addition to inducing AhR degradation, TCDD has been reported to induce degradation of hormone receptors. The studies reported here, evaluate the effect of TCDD exposure on androgen receptor (AR expression and activity in androgen-sensitive LNCaP and castration-resistant C4-2 prostate cancer cells. Our results show that TCDD exposure does not induce AhR or AR degradation in C4-2 cells. However, both AhR and AR are degraded in LNCaP cells following TCDD exposure. In addition, TCDD enhances AR phosphorylation and induces expression of AR responsive genes in LNCaP cells. Our data reveals that TCDD effect on AR expression and activity differs in androgen-sensitive and castration-resistant prostate cancer cell models.

  14. Favorable outcomes in locally advanced and node positive prostate cancer patients treated with combined pelvic IMRT and androgen deprivation therapy

    International Nuclear Information System (INIS)

    Lilleby, Wolfgang; Narrang, Amol; Tafjord, Gunnar; Vlatkovic, Ljiljana; Russnes, Kjell Magne; Stensvold, Andreas; Hole, Knut Håkon; Tran, Phuoc; Eilertsen, Karsten

    2015-01-01

    The most appropriate treatment for men with prostate cancer and positive pelvic nodes, N+, is an area of active controversy. We report our 5-years outcomes in men with locally advanced prostate cancer (T1-T4N0-N1M0) treated with definitive radiotherapy encompassing the prostate and pelvic lymph nodes (intensity modulated radiotherapy, IMRT) and long-term androgen deprivation therapy (ADT). Of the 138 consecutive eligible men all living patients have been followed up to almost 5 years. Survival endpoints for 5-year biochemical failure-free survival (BFFS), relapse-free survival (RFS), prostate cancer-specific survival (PCSS), and overall survival (OS) were assessed by Kaplan-Meier analysis. Univariate and multivariate Cox regression proportional hazards models were constructed for all survival endpoints. The RTOG morbidity grading system for physician rated toxicity was applied. Patients with locally advanced T3-T4 tumors (35 %) and N1 (51 %) have favorable outcome when long-term ADT is combined with definitive radiotherapy encompassing pelvic lymph nodes. The 5-year BFFS, RFS, PCSS and OS were 71.4, 76.2, 94.5 and 89.0 %, respectively. High Gleason sum (9–10) had a strong independent prognostic impact on BFFS, RFS and OS (p = 0.001, <0.001, and 0.005 respectively). The duration of ADT (= > 28 months) showed a significant independent association with improved PCSS (p = 0.02) and OS (p = 0.001). Lymph node involvement was not associated with survival endpoints in the multivariate analysis. The radiotherapy induced toxicity seen in our study population was moderate with rare Grade 3 GI side effects and up to 11 % for Grade 3 GU consisting mainly of urgency and frequency. Pelvic IMRT in combination with long-term ADT can achieve long-lasting disease control in men with N+ disease and unfavorable prognostic factors. The online version of this article (doi:10.1186/s13014-015-0540-3) contains supplementary material, which is available to authorized users

  15. Significance of pretreatment cardiovascular morbidity as a risk factor during treatment with parenteral oestrogen or combined androgen deprivation of 915 patients with metastasized prostate cancer

    DEFF Research Database (Denmark)

    Hedlund, Per Olov; Johansson, Robert; Damber, Jan Erik

    2011-01-01

    This study aimed to evaluate prognostic risk factors for cardiovascular events during treatment of metastatic prostate cancer patients with high-dose parenteral polyoestradiol phosphate (PEP, Estradurin®) or combined androgen deprivation (CAD) with special emphasis on pretreatment cardiovascular...

  16. Global analysis of transcription in castration-resistant prostate cancer cells uncovers active enhancers and direct androgen receptor targets.

    Science.gov (United States)

    Toropainen, Sari; Niskanen, Einari A; Malinen, Marjo; Sutinen, Päivi; Kaikkonen, Minna U; Palvimo, Jorma J

    2016-09-19

    Androgen receptor (AR) is a male sex steroid-activated transcription factor (TF) that plays a critical role in prostate cancers, including castration-resistant prostate cancers (CRPC) that typically express amplified levels of the AR. CRPC-derived VCaP cells display an excessive number of chromatin AR-binding sites (ARBs) most of which localize to distal inter- or intragenic regions. Here, we analyzed direct transcription programs of the AR in VCaP cells using global nuclear run-on sequencing (GRO-seq) and integrated the GRO-seq data with the ARB and VCaP cell-specific TF-binding data. Androgen immediately activated transcription of hundreds of protein-coding genes, including IGF-1 receptor and EGF receptor. Androgen also simultaneously repressed transcription of a large number of genes, including MYC. As functional enhancers have been postulated to produce enhancer-templated non-coding RNAs (eRNAs), we also analyzed the eRNAs, which revealed that only a fraction of the ARBs reside at functional enhancers. Activation of these enhancers was most pronounced at the sites that also bound PIAS1, ERG and HDAC3, whereas binding of HDAC3 and PIAS1 decreased at androgen-repressed enhancers. In summary, our genome-wide data of androgen-regulated enhancers and primary target genes provide new insights how the AR can directly regulate cellular growth and control signaling pathways in CPRC cells.

  17. Photoperiod modulation of aggressive behavior is independent of androgens in a tropical cichlid fish.

    Science.gov (United States)

    Gonçalves-de-Freitas, Eliane; Carvalho, Thaís Billalba; Oliveira, Rui F

    2014-10-01

    Photoperiod is a major environmental cue that signals breeding conditions in animals living in temperate climates. Therefore, the activity of the reproductive (i.e. hypothalamic-pituitary-gonadal, HPG) axis and of the expression of reproductive behaviors, including territoriality, is responsive to changes in day length. However, at low latitudes the seasonal variation in day length decreases dramatically and photoperiod becomes less reliable as a breeding entraining cue in tropical species. In spite of this, some tropical mammals and birds have been found to still respond to small amplitude changes in photoperiod (e.g. 17min). Here we tested the effect of 2 photoperiod regimes, referred to as long-day (LD: 16L:08D) and short-day (SD: 08L:16D), on the activity of the HPG axis, on aggressive behavior and in the androgen response to social challenges in males of the tropical cichlid fish Tilapia rendalli. For each treatment, fish were transferred from a pre-treatment photoperiod of 12L:12D to their treatment photoperiod (either LD or SD) in which they were kept for 20days on stock tanks. Afterwards, males were isolated for 4days in glass aquaria in order to establish territories and initial androgen levels (testosterone, T; 11-ketotestosterone, KT) were assessed. On the 4th day, territorial intrusions were promoted such that 1/3 of the isolated males acted as residents and another 1/3 as intruders. Territorial intrusions lasted for 1h to test the effects of a social challenge under different photoperiod regimes. Photoperiod treatment (either SD or LD) failed to induce significant changes in the HPG activity, as measured by androgen levels and gonadosomatic index. However, SD increased the intensity of aggressive behaviors and shortened the time to settle a dominance hierarchy in an androgen-independent manner. The androgen responsiveness to the simulated territorial intrusion was only present in KT but not for T. The percent change in KT levels in response to the

  18. National Trends and Predictors of Androgen Deprivation Therapy Use in Low-Risk Prostate Cancer.

    Science.gov (United States)

    Yang, David D; Muralidhar, Vinayak; Mahal, Brandon A; Labe, Shelby A; Nezolosky, Michelle D; Vastola, Marie E; King, Martin T; Martin, Neil E; Orio, Peter F; Choueiri, Toni K; Trinh, Quoc-Dien; Spratt, Daniel E; Hoffman, Karen E; Feng, Felix Y; Nguyen, Paul L

    2017-06-01

    Androgen deprivation therapy (ADT) is not recommended for low-risk prostate cancer because of its lack of benefit and potential for harm. We evaluated the incidence and predictors of ADT use in low-risk disease. Using the National Cancer Database, we identified 197,957 patients with low-risk prostate cancer (Gleason score of 3 + 3 = 6, prostate-specific antigen level used multiple logistic regression to evaluate predictors of ADT use and Cox regression to examine its association with all-cause mortality. Overall ADT use decreased from 17.6% in 2004 to 3.5% in 2012. In 2012, 11.5% of low-risk brachytherapy patients and 7.6% of external beam radiation therapy patients received ADT. Among 82,352 irradiation-managed patients, predictors of ADT use included treatment in a community versus academic cancer program (adjusted odds ratio [AOR], 1.60; 95% confidence interval [CI], 1.50-1.71; Puse versus external beam radiation therapy (AOR, 1.32; 95% CI, 1.27-1.37; Puse included a Charlson-Deyo comorbidity score of ≥2 versus 0 (AOR, 1.42; 95% CI, 1.06-1.91; P=.018); treatment in a community versus academic cancer program (AOR, 1.61; 95% CI, 1.37-1.90; Puse was associated with increased all-cause mortality in patients who did not receive local therapy (adjusted hazard ratio, 1.28; 95% CI, 1.14-1.43; Puse in low-risk prostate cancer has declined nationally but may remain an issue of concern in certain populations and regions. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Multivalent Peptidomimetic Conjugates as Inhibitors of Androgen Receptor Function in Therapy-Resistant Prostate Cancer

    Science.gov (United States)

    2017-10-01

    1 4. Impact…………………………………..………………………..4 5. Changes /Problems…………………………………..……..4 6. Products…………………………………..……………………..4 7. Participants & Other...AWARD NUMBER: W81XWH-15-1-0590 TITLE: Multivalent Peptidomimetic Conjugates as Inhibitors of Androgen Receptor Function in Therapy- Resistant ...in Therapy- Resistant Prostate Cancer 5b. GRANT NUMBER W81XWH-15-1-0590 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Michael Garabedian, PhD 5d

  20. Football training in men with prostate cancer undergoing androgen deprivation therapy

    DEFF Research Database (Denmark)

    Uth, Jacob; Hornstrup, Therese; Christensen, Jesper F

    2016-01-01

    ) and density, BTMs and postural balance. RESULTS: In the last part of the 12 weeks, FTG performed 194 ± 41 accelerations and 296 ± 65 decelerations at >0.6 m/s/s and covered a distance of 905 ± 297 m at speeds >6 km/h and 2646 ± 705 m per training session. Analysis of baseline-to-12-week change scores showed......PURPOSE: To investigate the activity profile of football training and its short-term effects on bone mass, bone turnover markers (BTMs) and postural balance in men with prostate cancer (PCa) undergoing androgen deprivation therapy (ADT). METHODS: This was a randomised 12-week study in which men...

  1. Androgen deprivation therapy for prostate cancer and the risk of hospitalisation for community-acquired pneumonia.

    Science.gov (United States)

    Hicks, Blánaid M; Yin, Hui; Bladou, Franck; Ernst, Pierre; Azoulay, Laurent

    2017-07-01

    Androgens have been shown to influence both the immune system and lung tissue, raising the hypothesis that androgen deprivation therapy (ADT) for prostate cancer may increase the risk of pneumonia. Thus, the aim of this study was to determine whether ADT is associated with an increased risk of hospitalisation for community-acquired pneumonia in patients with prostate cancer. This was a population-based cohort study using the United Kingdom Clinical Practice Research Datalink linked to the Hospital Episode Statistics repository. The cohort consisted of 20 310 men newly diagnosed with non-metastatic prostate cancer between 1 April 1998 and 31 March 2015. Time-dependent Cox proportional hazards models were used to estimate adjusted HRs and 95% CIs for hospitalisation for community-acquired pneumonia associated with current and past use of ADT compared with non-use. During a mean follow-up of 4.3 years, there were 621 incident hospitalisations for community-acquired pneumonia (incidence rate: 7.2/1000 person-years). Current ADT use was associated with an 81% increased risk of hospitalisation for community-acquired pneumonia (12.1 vs 3.8 per 1000 person-years, respectively; HR 1.81, 95% CI 1.47 to 2.23). The association was observed within the first six months of use (HR 1.73, 95% CI 1.23 to 2.42) and remained elevated with increasing durations of use (≥25 months; HR 1.79, 95% CI 1.39 to 2.30). In contrast, past ADT use was not associated with an increased risk (HR 1.23, 95% CI 0.95 to 1.60). The use of ADT is associated with an increased risk of hospitalisation for community-acquired pneumonia in men with prostate cancer. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  2. Beyond the androgen receptor II: New approaches to understanding and treating metastatic prostate cancer; Report from the 2017 Coffey-Holden Prostate Cancer Academy Meeting.

    Science.gov (United States)

    Miyahira, Andrea K; Cheng, Heather H; Abida, Wassim; Ellis, Leigh; Harshman, Lauren C; Spratt, Daniel E; Simons, Jonathan W; Pienta, Kenneth J; Soule, Howard R

    2017-11-01

    The 2017 Coffey-Holden Prostate Cancer Academy (CHPCA) Meeting, "Beyond the Androgen Receptor II: New Approaches to Understanding and Treating Metastatic Prostate Cancer," was held in Carlsbad, California from June 14-17, 2017. The CHPCA is an annual scientific conference hosted by the Prostate Cancer Foundation (PCF) that is uniquely designed to produce extensive and constructive discussions on the most urgent and impactful topics concerning research into the biology and treatment of metastatic prostate cancer. The 2017 CHPCA Meeting was the 5th meeting in this annual series and was attended by 71 investigators focused on prostate cancer and a variety of other fields including breast and ovarian cancer. The discussions at the meeting were concentrated on topics areas including: mechanisms and therapeutic approaches for molecular subclasses of castrate resistant prostate cancer (CRPC), the epigenetic landscape of prostate cancer, the role of DNA repair gene mutations, advancing the use of germline genetics in clinical practice, radionuclides for imaging and therapy, advances in molecular imaging, and therapeutic strategies for successful use of immunotherapy in advanced prostate cancer. This article reviews the presentations and discussions from the 2017 CHPCA Meeting in order to disseminate this knowledge and accelerate new biological understandings and advances in the treatment of patients with metastatic prostate cancer. © 2017 Wiley Periodicals, Inc.

  3. The association between inflammation-related genes and serum androgen levels in men: The Prostate, Lung, Colorectal, and Ovarian Study

    Science.gov (United States)

    Meyer, Tamra E.; Chu, Lisa W.; Li, Qizhai; Yu, Kai; Rosenberg, Philip S.; Menashe, Idan; Chokkalingam, Anand P.; Quraishi, Sabah M.; Huang, Wen-Yi; Weiss, Jocelyn M.; Kaaks, Rudolf; Hayes, Richard B.; Chanock, Stephen J.; Hsing, Ann W.

    2011-01-01

    BACKGROUND Androgens and inflammation have been implicated in the etiology of several cancers, including prostate cancer. Serum androgens have been shown to correlate with markers of inflammation and expression of inflammation-related genes. METHODS In this report, we evaluated associations between 9,932 single nucleotide polymorphisms (SNPs) marking common genetic variants in 774 inflammation-related genes and four serum androgen levels (total testosterone [T], bioavailable T [BioT]; 5α-androstane-3α, 17β-diol glucuronide [3αdiol G], and 4-Androstene-3,17-dione [androstenedione]), in 560 healthy men (median age 64 years) drawn from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Baseline serum androgens were measured by radioimmunoassay. Genotypes were determined as part of the Cancer Genetic Markers of Susceptibility Study genome-wide scan. SNP-hormone associations were evaluated using linear regression of hormones adjusted for age. Gene-based p-values were generated using an adaptive rank truncated product method. RESULTS Suggestive associations were observed for two inflammation-related genes and circulating androgen levels (false discovery rate [FDR] q-valueT in MMP2 and rs3822356T>C in CD14 (FDR q-value=0.09 for both SNPs). Other genes implicated in either SNP or gene-based tests were IK with T and BioT, PRG2 with T, and TNFSF9 with androstenedione. CONCLUSIONS These results suggest possible cross-talk between androgen levels and inflammation pathways, but larger studies are needed to confirm these findings and to further clarify the interrelationship between inflammation and androgens and their effects on cancer risk. PMID:21520164

  4. Androgen deprivation therapy for prostate cancer: recommendations to improve patient and partner quality of life.

    Science.gov (United States)

    Elliott, Stacy; Latini, David M; Walker, Lauren M; Wassersug, Richard; Robinson, John W

    2010-09-01

    Because of improved prostate cancer detection, more patients begin androgen deprivation therapy (ADT) earlier and remain on it longer than before. Patients now may be androgen deprived for over a decade, even when they are otherwise free of cancer symptoms. An ADT Survivorship Working Group was formed to develop and evaluate interventions to limit the physiological and emotional trauma patients and their partners experience from this treatment. The multidisciplinary Working Group met for 2 days to define the challenges couples face when patients commence ADT. A writing sub-group was formed. It compiled the meeting's proceedings, reviewed the literature and, in consultation with the other members of the working group, wrote the manuscript. Expert opinion of the side effects of ADT that affect the quality of life (QOL) of patients and their partners and the recommendations for managing ADT to optimize QOL were based on the best available literature, clinical experience, and widespread internal discussions among Working Group members. Side effects identified as particularly challenging include: (i) body feminization; (ii) changes in sexual performance; (iii) relationship changes; (iv) cognitive and affective symptoms; and (v) fatigue, sleep disturbance, and depression. Recommendations for managing ADT include providing information about ADT side effects before administration of ADT, and, where appropriate, providing referrals for psychosocial support. Sexual rehabilitation principles for persons with chronic illness may prove useful. Psychological interventions for sexual sequelae need to be offered and individualized to patients, regardless of their age or partnership. Support should also be offered to partners. Our hope is that this plan will serve as a guide for optimizing how ADT is carried out and improve the lives of androgen-deprived men and their intimate partners. © 2010 International Society for Sexual Medicine.

  5. Impact of Concurrent Androgen Deprivation on Fiducial Marker Migration in External-beam Radiation Therapy for Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Tiberi, David A.; Carrier, Jean-Francois; Beauchemin, Marie-Claude; Nguyen, Thu Van; Beliveau-Nadeau, Dominic [Departement de Radio-Oncologie, Centre hospitalier de l' Universite de Montreal-Hopital Notre-Dame, Montreal, Quebec (Canada); Taussky, Daniel, E-mail: daniel.taussky.chum@ssss.gouv.qc.ca [Departement de Radio-Oncologie, Centre hospitalier de l' Universite de Montreal-Hopital Notre-Dame, Montreal, Quebec (Canada)

    2012-09-01

    Purpose: To determine the extent of gold fiducial marker (FM) migration in patients treated for prostate cancer with concurrent androgen deprivation and external-beam radiation therapy (EBRT). Methods and Materials: Three or 4 gold FMs were implanted in 37 patients with prostate adenocarcinoma receiving androgen deprivation therapy (ADT) in conjunction with 70-78 Gy. Androgen deprivation therapy was started a median of 3.9 months before EBRT (range, 0.3-12.5 months). To establish the extent of FM migration, the distance between each FM was calculated for 5-8 treatments once per week throughout the EBRT course. For each treatment, the distance between FMs was compared with the distance from the digitally reconstructed radiographs generated from the planning CT. A total of 281 treatments were analyzed. Results: The average daily migration was 0.8 {+-} 0.3 mm, with distances ranging from 0.2 mm-2.6 mm. Two of the 281 assessed treatments (0.7%) showed migrations >2 mm. No correlation between FM migration and patient weight or time delay between ADT and start of EBRT was found. There was no correlation between the extent of FM migration and prostate volume. Conclusion: This is the largest report of implanted FM migration in patients receiving concomitant ADT. Only 0.7% of the 281 treatments studied had significant marker migrations (>2 mm) throughout the course of EBRT. Consequently, the use of implanted FMs in these patients enables accurate monitoring of prostate gland position during treatment.

  6. Critical role of androgen receptor level in prostate cancer cell resistance to new generation antiandrogen enzalutamide.

    Science.gov (United States)

    Hoefer, Julia; Akbor, Mohammady; Handle, Florian; Ofer, Philipp; Puhr, Martin; Parson, Walther; Culig, Zoran; Klocker, Helmut; Heidegger, Isabel

    2016-09-13

    Enzalutamide is an androgen receptor (AR) inhibitor approved for therapy of metastatic castration resistant prostate cancer. However, clinical application revealed that 30 to 40% of patients acquire resistance after a short period of treatment. Currently, the molecular mechanisms underlying such resistances are not completely understood, partly due to a lack of model systems. In the present study we established three different cellular models of enzalutamide resistance including a cell line with wild type AR (LAPC4), DuCaP cells which overexpress wild-type AR, as well as a cell which has been adapted to long term androgen ablation (LNCaP Abl) and harbors the AR T878A mutation. After 10 months of cultivation, sustained growth in the presence of enzalutamide was achieved. When compared to controls, resistant cells exhibit significantly decreased sensitivity to enzalutamide as measured with 3[H]thymidine incorporation and WST assay. Moreover, these cell models exhibit partly re-activated AR signaling despite presence of enzalutamide. In addition, we show that enzalutamide resistant cells are insensitive to bicalutamide but retain considerable sensitivity to abiraterone. Mechanistically, enzalutamide resistance was accompanied by increased AR and AR-V7 mRNA and protein expression as well as AR gene amplification, while no additional AR mutations have been identified.

  7. The Use of Dietary Supplements to Alleviate Androgen Deprivation Therapy Side Effects during Prostate Cancer Treatment

    Science.gov (United States)

    Dueregger, Andrea; Heidegger, Isabel; Ofer, Philipp; Perktold, Bernhard; Ramoner, Reinhold; Klocker, Helmut; Eder, Iris E.

    2014-01-01

    Prostate cancer (PCa), the most commonly diagnosed cancer and second leading cause of male cancer death in Western societies, is typically androgen-dependent, a characteristic that underlies the rationale of androgen deprivation therapy (ADT). Approximately 90% of patients initially respond to ADT strategies, however many experience side effects including hot flashes, cardiotoxicity, metabolic and musculoskeletal alterations. This review summarizes pre-clinical and clinical studies investigating the ability of dietary supplements to alleviate adverse effects arising from ADT. In particular, we focus on herbal compounds, phytoestrogens, selenium (Se), fatty acids (FA), calcium, and Vitamins D and E. Indeed, there is some evidence that calcium and Vitamin D can prevent the development of osteoporosis during ADT. On the other hand, caution should be taken with the antioxidants Se and Vitamin E until the basis underlying their respective association with type 2 diabetes mellitus and PCa tumor development has been clarified. However, many other promising supplements have not yet been subjected large-scale clinical trials making it difficult to assess their efficacy. Given the demographic trend of increased PCa diagnoses and dependence on ADT as a major therapeutic strategy, further studies are required to objectively evaluate these supplements as adjuvant for PCa patients receiving ADT. PMID:25338271

  8. Cav1.3 channel α1D protein is overexpressed and modulates androgen receptor transactivation in prostate cancers.

    Science.gov (United States)

    Chen, Ruibao; Zeng, Xing; Zhang, Ruitao; Huang, Jiaoti; Kuang, Xiangxing; Yang, Jun; Liu, Jihong; Tawfik, Ossama; Thrasher, James Brantley; Li, Benyi

    2014-07-01

    Widespread use of L-type calcium channel blockers for treating hypertension has led to multiple epidemiologic studies to assess the risk of prostate cancer incidence. These studies revealed a reverse correlation between the likelihood of prostate cancer risk and the use of L-type calcium channel blockers among men without family history but the mechanism was not clear. In this study, we examined the expression profiles of multiple L-type calcium channel genes in prostate cancers and determined their functional roles in androgen receptor (AR) transactivation and cell growth. By reanalyzing the ONCOMINE database, we found that L-type calcium channel CACNA1D gene expression levels in cancer tissues were significantly higher than noncancer tissues in 14 of 15 published complementary deoxyribonucleic acid microarray data sets, of which 9 data sets showed an increase of 2- to 17-folds. Quantitative polymerase chain reaction and immunostaining experiments revealed that CACNA1D gene and its coding protein α1D were highly expressed in prostate cancers, especially in castration-resistant diseases, compared with benign prostate tissues. Consistent with the notion of CACNA1D as an ERG-regulated gene, CACNA1D gene expression levels were significantly higher in prostate cancers with TMPRSS2-ERG gene fusion compared with the cases without this gene fusion. Blocking L-type channel's function or knocking down CACNA1D gene expression significantly suppressed androgen-stimulated Ca(2+) influx, AR transactivation, and cell growth in prostate cancer cells. Taken together, these data suggest that CACNA1D gene overexpression is associated with prostate cancer progression and might play an important role in Ca(2+) influx, AR activation, and cell growth in prostate cancer cells. Copyright © 2014 Elsevier Inc. All rights reserved.

  9. A pilot study of exercise in men with prostate cancer receiving androgen deprivation therapy

    International Nuclear Information System (INIS)

    Lee, C Ellen; Leslie, William D; Lau, YK James

    2012-01-01

    Androgen deprivation therapy (ADT) is the mainstay therapy for men with prostate cancer. However, there are musculoskeletal side effects from ADT that increase the risk for osteoporosis and fracture, and can compromise the quality of life of these individuals. The objectives of this study are to determine the efficacy of a home-based walking exercise program in promoting bone health, physical function and quality of life in men with prostate cancer receiving ADT. A 12-month prospective, single-blinded, randomized controlled trial will be conducted to compare the Exercise Group with the Control Group. Sixty men with prostate cancer who will be starting ADT will be recruited and randomly assigned to one of the two groups: the Exercise Group will receive instructions in setting up an individualized 12-month home-based walking exercise program, while the Control Group will receive standard medical advice from the attending physician. A number of outcome measures will be used to assess bone health, physical function, and health-related quality of life. At baseline and 12 months, bone health will be assessed using dual-energy X-ray absorptiometry. At baseline and every 3 months up to 12 months, physical function will be evaluated using the Functional Assessment of Chronic Illness Therapy - Fatigue Scale, Activities-specific Balance Confidence Scale, Short Physical Performance Battery, and Six-Minute Walk Test; and health-related quality of life will be assessed using the Functional Assessment of Cancer Therapy Prostate Module and the Medical Outcomes Study 12-item Short Form Health Survey Version 2. A mixed multiple analysis of variance will be used to analyze the data. Musculoskeletal health management remains a challenge in men with prostate cancer receiving ADT. This study addresses this issue by designing a simple and accessible home-based walking exercise program that will potentially have significant impact on reducing the risk of fracture, promoting physical

  10. MicroPET assessment of androgenic control of glucose and acetate uptake in the rat prostate and a prostate cancer tumor model

    Energy Technology Data Exchange (ETDEWEB)

    Oyama, Nobuyuki; Kim, Joonyoung; Jones, Lynne A.; Mercer, Nicole M.; Engelbach, John A.; Sharp, Terry L.; Welch, Michael J. E-mail: welchm@mir.wustl.edu

    2002-11-01

    PET has been used to monitor changes in tumor metabolism in breast cancer following hormonal therapy. This study was undertaken to determine whether PET imaging could evaluate early metabolic changes in prostate tumor following androgen ablation therapy. Studies were performed comparing two positron-emitting tracers, {sup 18}F-FDG and {sup 11}C-acetate, in Sprague-Dawley male rats to monitor metabolic changes in normal prostate tissue. Additional studies were performed in nude mice bearing the CWR22 androgen-dependent human prostate tumor to evaluate metabolic changes in prostate tumor. In rats, for the androgen ablation pretreatment, 1 mg diethylstilbestrol (DES) was injected subcutaneously 3 and 24 hours before tracer injection. For androgen pretreatment, 500 {mu}g dihydrotestosterone (DHT) was injected intraperitoneally 2 and 6 hours before tracer injection. The rats were divided into three groups, Group A (no-DES, no-DHT, n = 18), Group B (DES, no-DHT, n = 18) and Group C (DES, DHT, n = 18). In each group, 10 animals received {sup 18}F-FDG, whereas the remaining eight animals were administered {sup 11}C-acetate. Rats were sacrificed at 120 min post-injection of {sup 18}F-FDG or 30 min post-injection of {sup 11}C-acetate. Pretreatment of the mouse model using DHT (200 {mu}g of DHT in 0.1 mL of sunflower seed oil) or DES (200 {mu}g of DES in 0.1 mL of sunflower seed oil) was conducted every 2 days for one week. Mice were imaged with both tracers in the microPET scanner (Concorde Microsystems Inc.). DES treatment caused a decrease in acetate and glucose metabolism in the rat prostate. Co-treatment with DHT maintained the glucose metabolism levels at baseline values. In the tumor bearing mice, similar effects were seen in {sup 18}F-FDG study, while there was no significant difference in {sup 11}C-acetate uptake. These results indicate that changes in serum testosterone levels influence {sup 18}F-FDG uptake in the prostate gland, which is closely tied to glucose

  11. Clinical Outcomes and Testosterone Levels Following Continuous Androgen Deprivation in Patients with Relapsing or Locally Advanced Prostate Cancer: A Post Hoc Analysis of the ICELAND Study.

    Science.gov (United States)

    Tombal, Bertrand; Cornel, Erik B; Persad, Raj; Stari, Anny; Gómez Veiga, Francisco; Schulman, Claude

    2017-11-01

    Lower serum testosterone levels correlate with improved cause specific survival and longer time to progression in year 1 of continuous androgen deprivation in men with prostate cancer. ICELAND was a large European study demonstrating the efficacy of leuprorelin (Eligard®) during continuous androgen deprivation. In this post hoc analysis we investigated serum testosterone levels within year 1 of continuous androgen deprivation to determine survival and time to progression. In ICELAND (ClinicalTrials.gov NCT00378690) patients with locally advanced or relapsing nonmetastatic prostate cancer and with prostate specific antigen 1 ng/ml or less following 6-month induction with leuprorelin 3-month depot 22.5 mg (plus bicalutamide 50 mg per day for 1 month) were randomized 1:1 to continuous androgen deprivation (361) or intermittent androgen deprivation (340) with leuprorelin for 36 months. Patients receiving continuous androgen deprivation were stratified by minimum, median and maximum testosterone levels during year 1 of therapy into 20 or less, greater than 20 to 50 and greater than 50 ng/dl subgroups. Cause specific survival and time to prostate specific antigen (castrate resistant prostate cancer) progression were analyzed. A total of 90.1%, 83.5% and 74.5% of patients receiving continuous androgen deprivation achieved minimum, median and maximum serum testosterone levels of 20 ng/dl or less, respectively. Cause specific survival rates and time to prostate specific antigen progression did not differ among the testosterone subgroups. In patients receiving continuous androgen deprivation cause specific survival and time to prostate specific antigen progression did not differ according to testosterone levels in year 1 of therapy. This finding may in part be due to the induction period and the effectiveness of leuprorelin in lowering testosterone. Copyright © 2017 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  12. Gonadotropin-releasing hormone antagonists versus standard androgen suppression therapy for advanced prostate cancer A systematic review with meta-analysis.

    Science.gov (United States)

    Kunath, Frank; Borgmann, Hendrik; Blümle, Anette; Keck, Bastian; Wullich, Bernd; Schmucker, Christine; Sikic, Danijel; Roelle, Catharina; Schmidt, Stefanie; Wahba, Amr; Meerpohl, Joerg J

    2015-11-13

    To evaluate efficacy and safety of gonadotropin-releasing hormone (GnRH) antagonists compared to standard androgen suppression therapy for advanced prostate cancer. The international review team included methodologists of the German Cochrane Centre and clinical experts. We searched CENTRAL, MEDLINE, Web of Science, EMBASE, trial registries and conference books for randomised controlled trials (RCT) for effectiveness data analysis, and randomised or non-randomised controlled studies (non-RCT) for safety data analysis (March 2015). Two authors independently screened identified articles, extracted data, evaluated risk of bias and rated quality of evidence according to GRADE. 13 studies (10 RCTs, 3 non-RCTs) were included. No study reported cancer-specific survival or clinical progression. There were no differences in overall mortality (RR 1.35, 95% CI 0.63 to 2.93), treatment failure (RR 0.91, 95% CI 0.70 to 1.17) or prostate-specific antigen progression (RR 0.83, 95% CI 0.64 to 1.06). While there was no difference in quality of life related to urinary symptoms, improved quality of life regarding prostate symptoms, measured with the International Prostate Symptom Score (IPSS), with the use of GnRH antagonists compared with the use of standard androgen suppression therapy (mean score difference -0.40, 95% CI -0.94 to 0.14, and -1.84, 95% CI -3.00 to -0.69, respectively) was found. Quality of evidence for all assessed outcomes was rated low according to GRADE. The risk for injection-site events was increased, but cardiovascular events may occur less often by using GnRH antagonist. Available evidence is hampered by risk of bias, selective reporting and limited follow-up. There is currently insufficient evidence to make firm conclusive statements on the efficacy of GnRH antagonist compared to standard androgen suppression therapy for advanced prostate cancer. There is need for further high-quality research on GnRH antagonists with long-term follow-up. CRD42012002751

  13. Gonadotropin-releasing hormone antagonists versus standard androgen suppression therapy for advanced prostate cancer A systematic review with meta-analysis

    Science.gov (United States)

    Kunath, Frank; Borgmann, Hendrik; Blümle, Anette; Keck, Bastian; Wullich, Bernd; Schmucker, Christine; Sikic, Danijel; Roelle, Catharina; Schmidt, Stefanie; Wahba, Amr; Meerpohl, Joerg J

    2015-01-01

    Objectives To evaluate efficacy and safety of gonadotropin-releasing hormone (GnRH) antagonists compared to standard androgen suppression therapy for advanced prostate cancer. Setting The international review team included methodologists of the German Cochrane Centre and clinical experts. Participants We searched CENTRAL, MEDLINE, Web of Science, EMBASE, trial registries and conference books for randomised controlled trials (RCT) for effectiveness data analysis, and randomised or non-randomised controlled studies (non-RCT) for safety data analysis (March 2015). Two authors independently screened identified articles, extracted data, evaluated risk of bias and rated quality of evidence according to GRADE. Results 13 studies (10 RCTs, 3 non-RCTs) were included. No study reported cancer-specific survival or clinical progression. There were no differences in overall mortality (RR 1.35, 95% CI 0.63 to 2.93), treatment failure (RR 0.91, 95% CI 0.70 to 1.17) or prostate-specific antigen progression (RR 0.83, 95% CI 0.64 to 1.06). While there was no difference in quality of life related to urinary symptoms, improved quality of life regarding prostate symptoms, measured with the International Prostate Symptom Score (IPSS), with the use of GnRH antagonists compared with the use of standard androgen suppression therapy (mean score difference −0.40, 95% CI −0.94 to 0.14, and −1.84, 95% CI −3.00 to −0.69, respectively) was found. Quality of evidence for all assessed outcomes was rated low according to GRADE. The risk for injection-site events was increased, but cardiovascular events may occur less often by using GnRH antagonist. Available evidence is hampered by risk of bias, selective reporting and limited follow-up. Conclusions There is currently insufficient evidence to make firm conclusive statements on the efficacy of GnRH antagonist compared to standard androgen suppression therapy for advanced prostate cancer. There is need for further high-quality research on

  14. The Effects of the Organic Flame-Retardant 1,2-Dibromo-4-(1,2-dibromoethyl) Cyclohexane (TBECH) on Androgen Signaling in Human Prostate Cancer Cell Lines.

    Science.gov (United States)

    Wong, Lilian I L; Reers, Alexandra R; Currier, Heidi A; Williams, Tony D; Cox, Michael E; Elliott, John E; Beischlag, Timothy V

    2016-05-01

    The effects of the organic flame retardant 1,2-Dibromo-4-(1,2-dibromoethyl) cyclohexane (TBECH) on androgen receptor target gene expression were examined in the human LNCaP prostate cancer cell line. While γ-/δ-TBECH alone led to a significant increase in prostate-specific antigen (PSA) mRNA accumulation, both the α-/-TBECH and γ-/δ-TBECH mixtures repressed androgen-inducible PSA mRNA and protein accumulation in human LNCaP cells. Thus, we hypothesize that isomeric mixtures of TBECH may act as partial agonists of the androgen receptor. © 2015 Wiley Periodicals, Inc.

  15. Cognitive Impairment in Men with Prostate Cancer Treated with Androgen Deprivation Therapy: A Systematic Review and Meta-Analysis.

    Science.gov (United States)

    Sun, Maxine; Cole, Alexander P; Hanna, Nawar; Mucci, Lorelei A; Berry, Donna L; Basaria, Shehzad; Ahern, David K; Kibel, Adam S; Choueiri, Toni K; Trinh, Quoc-Dien

    2018-02-02

    Use of androgen deprivation therapy may increase the risk of cognitive impairment in men with prostate cancer. We performed a systematic review of the risk of overall cognitive impairment as an outcome in men receiving androgen deprivation therapy for prostate cancer. Studies were identified through PubMed®, MEDLINE®, PsycINFO®, Cochrane Library and Web of Knowledge/Science™. Articles were included if they 1) were published in English, 2) had subjects treated for prostate cancer with androgen deprivation therapy, 3) incorporated longitudinal comparisons and 4) used control groups. In addition, prospective studies were required to assess an established cognitive related end point using International Cognition and Cancer Task Force criteria defining impaired cognitive performance as scoring 1.5 or more standard deviations below published norms on 2 or more tests, or scoring 2.0 or more standard deviations below published norms on at least 1 test. The effect of androgen deprivation therapy on cognitive impairment was pooled using a random effects model. Of 221 abstracts 26 were selected for full text review, and 2 prospective and 4 retrospective studies were analyzed. Androgen deprivation therapy was not associated with overall cognitive impairment when the prospective cohort studies were pooled (OR 1.57, 95% CI 0.50 to 4.92, p = 0.44) with significant heterogeneity between estimates (I 2 = 83%). In retrospective data the relative risk of any cognitive impairment, including senile dementia and Alzheimer disease, was increased in men receiving androgen deprivation therapy, although the difference was not statistically significant (HR 1.28, 95% CI 0.93 to 1.76, p = 0.13) with moderate heterogeneity between estimates (I 2 = 67%). Analyses between overall cognitive impairment and use of androgen deprivation therapy defined according to International Cognition and Cancer Task Force criteria in a pooled analysis were inconclusive. In retrospective cohort studies the

  16. 20-Aminosteroids as a novel class of selective and complete androgen receptor antagonists and inhibitors of prostate cancer cell growth.

    Science.gov (United States)

    Fousteris, Manolis A; Schubert, Undine; Roell, Daniela; Roediger, Julia; Bailis, Nikolaos; Nikolaropoulos, Sotiris S; Baniahmad, Aria; Giannis, Athanassios

    2010-10-01

    Here, the synthesis and the evaluation of novel 20-aminosteroids on androgen receptor (AR) activity is reported. Compounds 11 and 18 of the series inhibit both the wild type and the T877A mutant AR-mediated transactivation indicating AR antagonistic function. Interestingly, minor structural changes such as stereoisomers of the amino lactame moiety exhibit preferences for antagonism among wild type and mutant AR. Other tested nuclear receptors are only weakly or not affected. In line with this, the prostate cancer cell growth of androgen-dependent but not of cancer cells lacking expression of the AR is inhibited. Further, the expression of the prostate specific antigen used as a diagnostic marker is also repressed. Finally steroid 18 enhances cellular senescence that might explain in part the growth inhibition mediated by this derivative. Steroids 11 and 18 are the first steroids that act as complete AR antagonists and exhibit AR specificity. Copyright © 2010 Elsevier Ltd. All rights reserved.

  17. Endurance training improves insulin sensitivity and body composition in prostate cancer patients treated with androgen deprivation therapy

    DEFF Research Database (Denmark)

    Hvid, Thine; Winding, Kamilla; Rinnov, Anders

    2013-01-01

    Insulin resistance and changes in body composition are side effects of androgen deprivation therapy (ADT) given to prostate cancer patients. The present study investigated whether endurance training improves insulin sensitivity and body composition in ADT-treated prostate cancer patients. Nine men...... and magnetic resonance imaging). The secondary endpoint was systemic inflammation. Statistical analysis was carried out using two-way ANOVA. Endurance training increased VO2max (ml(O2)/min per kg) by 11 and 13% in the patients and controls respectively (P...

  18. Prospective study of exercise intervention in prostate cancer patients on androgen deprivation therapy

    International Nuclear Information System (INIS)

    Beydoun, Nadine; Bucci, Joseph A.; Chin, Yaw S.; Spry, Nigel; Newton, Robert; Galvão, Daniel A.

    2014-01-01

    Androgen deprivation therapy (ADT) is an important component of modern prostate cancer treatment. Survival benefits from neo-adjuvant and adjuvant hormones may take years to manifest, and balancing this with potential morbidity of therapy can be challenging. This study aimed to assess whether education and short-term combined aerobic and resistance exercises could help to ameliorate the adverse side effects of ADT. Eight hundred fifty-nine patients with relapsed or metastatic prostate cancer on leuprorelin acetate were allocated to three interventional streams based on patient preference and medical fitness: supervised group (Face-to-Face) exercise sessions, home-based (At Home) exercise or a support programme for those incapable of exercising (Support). Patients enrolled onto Face to Face underwent measurement of body composition and cardiorespiratory fitness variables at baseline and programme completion. Patients in the exercise streams were surveyed to determine the programme's impact on physical fitness and well-being. Statistically significant improvements (p<0.001) were seen in all measured cardiorespiratory fitness and strength variables. Programme attrition rates were low (75/859; 8.7%), the primary reason for withdrawal being discontinuation of hormones (70%). Programme satisfaction was high, with 98% of surveyed patients reporting a positive impact on fitness and 97% planning to continue exercising after programme completion. At 6 months, improved physical and emotional well-being was reported by 93 and 79% of patients, respectively. A short-term structured exercise intervention results in high compliance and significant improvements in muscle strength and cardiorespiratory fitness in prostate cancer patients on ADT.

  19. [Osteoporosis fracture in a male patient secondary to hypogonadism due to androgen deprivation treatment for prostate cancer].

    Science.gov (United States)

    Verdú Solans, J; Roig Grau, I; Almirall Banqué, C

    2014-01-01

    A 84 year-old patient, in therapy with androgen deprivation during the last 5 years due a prostate cancer, is presented with a osteoporotic fracture of the first lumbar vertebra. The pivotal role of the primary care physician, in the prevention of the osteoporosis secondary to the hypogonadism in these patients, is highlighted. Copyright © 2012 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España. All rights reserved.

  20. Cystatin C Is Downregulated in Prostate Cancer and Modulates Invasion of Prostate Cancer Cells via MAPK/Erk and Androgen Receptor Pathways

    OpenAIRE

    Wegiel, Barbara; Jiborn, Thomas; Abrahamson, Magnus; Helczynski, Leszek; Otterbein, Leo; Persson, Jenny Liao; Bjartell, Anders

    2009-01-01

    Cystatin C is believed to prevent tumor progression by inhibiting the activities of a family of lysosomal cysteine proteases. However, little is known about the precise mechanism of cystatin C function in prostate cancer. In the present study, we examined the expression of cystatin C and its association with matrix metalloproteinases 2 (MMP2) and androgen receptor (AR) in a tissue microarray comparing benign and malignant specimens from 448 patients who underwent radical prostatectomy for loc...

  1. The Isolation and Characterization of Human Prostate Cancer Stem Cells

    Science.gov (United States)

    2011-02-01

    only a small subset of cells from established prostate cancer cell lines and xeno - grafts possess tumor initiating ability [6,7]. At present, no group...Reiter RE, Sawyers CL. Evidence for clonal outgrowth of androgen -independent prostate cancer cells from androgen - dependent tumors through a two-step

  2. Poly[3-(3, 4-dihydroxyphenyl) glyceric acid] from Comfrey exerts anti-cancer efficacy against human prostate cancer via targeting androgen receptor, cell cycle arrest and apoptosis.

    Science.gov (United States)

    Shrotriya, Sangeeta; Gagan, Deep; Ramasamy, Kumaraguruparan; Raina, Komal; Barbakadze, Vakhtang; Merlani, Maia; Gogilashvili, Lali; Amiranashvili, Lela; Mulkijanyan, Karen; Papadopoulos, Kyriakos; Agarwal, Chapla; Agarwal, Rajesh

    2012-08-01

    The major obstacles in human prostate cancer (PCA) treatment are the development of resistance to androgen ablation therapy leading to hormone-refractory state and the toxicity associated with chemotherapeutic drugs. Thus, the identification of additional non-toxic agents that are effective against both androgen-dependent and androgen-independent PCA is needed. In the present study, we investigated the efficacy of a novel phytochemical poly[3-(3, 4-dihydroxyphenyl)glyceric acid] (p-DGA) from Caucasian species of comfrey (Symphytum caucasicum) and its synthetic derivative syn-2, 3-dihydroxy-3-(3, 4-dihydroxyphenyl) propionic acid (m-DGA) against PCA LNCaP and 22Rv1 cells. We found that both p-DGA and m-DGA suppressed the growth and induced death in PCA cells, with comparatively lesser cytotoxicity towards non-neoplastic human prostate epithelial cells. Furthermore, we also found that both p-DGA and m-DGA caused G(1) arrest in PCA cells through modulating the expression of cell cycle regulators, especially an increase in CDKIs (p21 and p27). In addition, p-DGA and m-DGA induced apoptotic death by activating caspases, and also strongly decreased AR and PSA expression. Consistent with in vitro results, our in vivo study showed that p-DGA feeding strongly inhibited 22Rv1 tumors growth by 76% and 88% at 2.5 and 5mg/kg body weight doses, respectively, without any toxicity, together with a strong decrease in PSA level in plasma; and a decrease in PCNA, AR and PSA expression but increase in p21/p27 expression and apoptosis in tumor tissues from p-DGA-fed mice. Overall, present study identifies p-DGA as a potent agent against PCA without any toxicity, and supports its clinical application.

  3. The prostate after administration of anabolic androgenic steroids: a morphometrical study in rats

    Directory of Open Access Journals (Sweden)

    Rafael Areas Vargas

    2013-09-01

    Full Text Available Purpose Many adverse effects have been associated with abuse of anabolic-androgenic steroids (AAS, including disorders of the urogenital tract. The objective of this study is to analyze the morphological modifications in the prostate ventral lobe of pubertal and adult rats chronically treated with AAS, using morphometric methods. Materials and Methods: We studied 39 male Wistar rats weighing between 400 g and 550 g. The rats were divided into four groups: (a control rats, with 105 days of age (C105 (n = 7; (b control rats with 65 days of age (C65 (n = 9, injected only with the vehicle (peanut oil; (c treated rats, with 105 days of age (T105 (n = 10 and (d treated rats with 65 days of age (T65 (n = 13. The treated rats were injected with nandrolone decanoate at a dose of 10 mg.Kg-1 body weight. The steroid hormone and the vehicle were administered by intramuscular injection once a week for eight weeks. The rats were killed at 161 days of age (C105 and T105 and 121 days of age (C65 and T65 and the ventral prostate lobe was dissected and processed for histology. The height of the acinar epithelium, the surface densities of the lumen, epithelium and stroma were observed with X400 magnification using an Olympus light microscope coupled to a Sony CCD video camera, and the images transferred to a Sony monitor KX14-CP1. The selected histological areas were then quantified using the M42 test-grid system on the digitized fields. The data were analyzed with the Graphpad software. To compare the quantitative data in both groups (controls and treated and the outcomes, Student's t-test was used (p < 0.05 was considered significant. Results: The weight (p < 0.001 and volume (p = 0.004 of the prostate ventral lobe showed differences between C65 and T65 groups and between C105 and T105 groups. The epithelium height showed no difference between groups C65 and T65 (p = 0.8509, but the T105 group showed an increase of 32% compared to C105 (p = 0.0089. Concerning

  4. Type I Collagen Synthesis Marker Procollagen I N-Terminal Peptide (PINP) in Prostate Cancer Patients Undergoing Intermittent Androgen Suppression

    Energy Technology Data Exchange (ETDEWEB)

    Hamilton, Gerhard, E-mail: gerhard.hamilton@toc.lbg.ac.at; Olszewski-Hamilton, Ulrike [Ludwig Boltzmann Cluster of Translational of Oncology, Nussdorfer Strasse 64, Vienna A-1090 (Austria); Theyer, Gerhard [Hospital Kittsee, Kittsee A-2421, Burgenland (Austria)

    2011-09-15

    Intermittent androgen suppression (IAS) therapy for prostate cancer patients attempts to maintain the hormone dependence of the tumor cells by cycles alternating between androgen suppression (AS) and treatment cessation till a certain prostate-specific antigen (PSA) threshold is reached. Side effects are expected to be reduced, compared to standard continuous androgen suppression (CAS) therapy. The present study examined the effect of IAS on bone metabolism by determinations of serum procollagen I N-terminal peptide (PINP), a biochemical marker of collagen synthesis. A total of 105 treatment cycles of 58 patients with prostate cancer stages ≥pT2 was studied assessing testosterone, PSA and PINP levels at monthly intervals. During phases of AS lasting for up to nine months PSA levels were reversibly reduced, indicating apoptotic regression of the prostatic tumors. Within the first cycle PINP increased at the end of the AS period and peaked in the treatment cessation phase. During the following two cycles a similar pattern was observed for PINP, except a break in collagen synthesis as indicated by low PINP levels in the first months off treatment. Therefore, measurements of the serum PINP concentration indicated increased bone matrix synthesis in response to >6 months of AS, which uninterruptedly continued into the first treatment cessation phase, with a break into each of the following two pauses. In summary, synthesis of bone matrix collagen increases while degradation decreases during off-treatment phases in patients undergoing IAS. Although a direct relationship between bone matrix turnover and risk of fractures is difficult to establish, IAS for treatment of biochemical progression of prostate tumors is expected to reduce osteoporosis in elderly men often at high risk for bone fractures representing a highly suitable patient population for this kind of therapy.

  5. External Beam Radiation Therapy and Abiraterone in Men With Localized Prostate Cancer: Safety and Effect on Tissue Androgens

    International Nuclear Information System (INIS)

    Cho, Eunpi; Mostaghel, Elahe A.; Russell, Kenneth J.; Liao, Jay J.; Konodi, Mark A.; Kurland, Brenda F.; Marck, Brett T.; Matsumoto, Alvin M.; Dalkin, Bruce L.; Montgomery, R. Bruce

    2015-01-01

    Purpose: Optimizing androgen suppression may provide better control of localized prostate cancer (PCa). Numerous trials have supported the benefit of combining androgen deprivation therapy with definitive radiation therapy in men with locally advanced or high-grade disease. Addition of abiraterone to luteinizing hormone-releasing hormone agonist (LHRHa) with radiation has not been reported. We examined the safety of this combination as well as its impact on androgen suppression. Methods and Materials: A prospective, phase 2 study was conducted in men with localized PCa treated with 6 months of neoadjuvant and concurrent abiraterone with LHRHa and radiation. Duration of adjuvant LHRHa was at the discretion of the treating clinician. Prostate biopsy assays were obtained prior to the start of therapy and prior to radiation. Sera and tissue androgen levels were measured by liquid chromatography-tandem mass spectrometry. Results: A total of 22 men with intermediate- (n=3) and high-risk PCa (n=19) received study therapy. Sixteen men completed the intended course of abiraterone, and 19 men completed planned radiation to 77.4 to 81 Gy. Radiation to pelvic nodes was administered in 20 men. The following grade 3 toxicities were reported: lymphopenia (14 patients), fatigue (1 patient), transaminitis (2 patients), hypertension (2 patients), and hypokalemia (1 patient). There were no grade 4 toxicities. All 21 men who complied with at least 3 months of abiraterone therapy had a preradiation prostate-specific antigen (PSA) concentration nadir of <0.3 ng/mL. Median levels of tissue androgen downstream of CYP17A were significantly suppressed after treatment with abiraterone, and upstream steroids were increased. At median follow-up of 21 months (range: 3-37 months), only 1 patient (who had discontinued abiraterone at 3 months) had biochemical relapse. Conclusions: Addition of abiraterone to LHRHa with radiation is safe and achieves effective prostatic androgen suppression

  6. External Beam Radiation Therapy and Abiraterone in Men With Localized Prostate Cancer: Safety and Effect on Tissue Androgens

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Eunpi [University of Washington School of Medicine, Seattle, Washington (United States); Fred Hutchinson Cancer Research Center, Seattle, Washington (United States); Mostaghel, Elahe A. [Fred Hutchinson Cancer Research Center, Seattle, Washington (United States); Russell, Kenneth J.; Liao, Jay J.; Konodi, Mark A. [University of Washington School of Medicine, Seattle, Washington (United States); Kurland, Brenda F. [University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Marck, Brett T. [Veterans Affairs Puget Sound Health Care System, Seattle, Washington (United States); Matsumoto, Alvin M. [University of Washington School of Medicine, Seattle, Washington (United States); Veterans Affairs Puget Sound Health Care System, Seattle, Washington (United States); Dalkin, Bruce L. [University of Washington School of Medicine, Seattle, Washington (United States); Montgomery, R. Bruce, E-mail: rbmontgo@uw.edu [University of Washington School of Medicine, Seattle, Washington (United States)

    2015-06-01

    Purpose: Optimizing androgen suppression may provide better control of localized prostate cancer (PCa). Numerous trials have supported the benefit of combining androgen deprivation therapy with definitive radiation therapy in men with locally advanced or high-grade disease. Addition of abiraterone to luteinizing hormone-releasing hormone agonist (LHRHa) with radiation has not been reported. We examined the safety of this combination as well as its impact on androgen suppression. Methods and Materials: A prospective, phase 2 study was conducted in men with localized PCa treated with 6 months of neoadjuvant and concurrent abiraterone with LHRHa and radiation. Duration of adjuvant LHRHa was at the discretion of the treating clinician. Prostate biopsy assays were obtained prior to the start of therapy and prior to radiation. Sera and tissue androgen levels were measured by liquid chromatography-tandem mass spectrometry. Results: A total of 22 men with intermediate- (n=3) and high-risk PCa (n=19) received study therapy. Sixteen men completed the intended course of abiraterone, and 19 men completed planned radiation to 77.4 to 81 Gy. Radiation to pelvic nodes was administered in 20 men. The following grade 3 toxicities were reported: lymphopenia (14 patients), fatigue (1 patient), transaminitis (2 patients), hypertension (2 patients), and hypokalemia (1 patient). There were no grade 4 toxicities. All 21 men who complied with at least 3 months of abiraterone therapy had a preradiation prostate-specific antigen (PSA) concentration nadir of <0.3 ng/mL. Median levels of tissue androgen downstream of CYP17A were significantly suppressed after treatment with abiraterone, and upstream steroids were increased. At median follow-up of 21 months (range: 3-37 months), only 1 patient (who had discontinued abiraterone at 3 months) had biochemical relapse. Conclusions: Addition of abiraterone to LHRHa with radiation is safe and achieves effective prostatic androgen suppression

  7. Nutrition therapy with high intensity interval training to improve prostate cancer-related fatigue in men on androgen deprivation therapy: a study protocol

    OpenAIRE

    Baguley, Brenton J.; Skinner, Tina L.; Leveritt, Michael D.; Wright, Olivia R. L.

    2017-01-01

    Background Cancer-related fatigue is one of the most prevalent, prolonged and distressing side effects of prostate cancer treatment with androgen deprivation therapy. Preliminary evidence suggests natural therapies such as nutrition therapy and structured exercise prescription can reduce symptoms of cancer-related fatigue. Men appear to change their habitual dietary patterns after prostate cancer diagnosis, yet prostate-specific dietary guidelines provide limited support for managing adverse ...

  8. Implementation of High-Dose-Rate Brachytherapy and Androgen Deprivation in Patients With Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Lilleby, Wolfgang, E-mail: wolfgang.lilleby@ous-hf.no [Cancer Clinic, Oslo University Hospital, Norwegian Radiumhospital, Department of Radiotherapy and Oncology, Oslo (Norway); Tafjord, Gunnar; Raabe, Nils K. [Cancer Clinic, Oslo University Hospital, Norwegian Radiumhospital, Department of Radiotherapy and Oncology, Oslo (Norway)

    2012-07-01

    Purpose: To evaluate outcome (overall survival [OS], the actuarial 5-year cancer-specific survival [CSS], disease-free survival [DFS], biochemical failure-free survival [BFS]), complications and morbidity in patients treated with high-dose-rate brachytherapy (HDR-BT) boost and hormonal treatment with curative aims. Methods: Between 2004 and 2009, 275 prospectively followed pN0/N0M0 patients were included: 19 patients (7%) with T2, Gleason score 7 and prostate-specific antigen (PSA) <10 and 256 patients (93%) with T3 or Gleason score 8-10 or PSA >20 received multimodal treatment with conformal four-field radiotherapy (prostate/vesiculae 2 Gy Multiplication-Sign 25) combined with HDR-BT (iridium 192; prostate 10 Gy Multiplication-Sign 2) with long-term androgen deprivation therapy (ADT). Results: After a median observation time of 44.2 months (range, 10.4-90.5 months) 12 patients had relapsed clinically and/or biochemically and 10 patients were dead, of which 2 patients died from prostate cancer. Five-year estimates of BFS, CSS, DFS, and OS rates were 98.5%, 99.3%, 95.6%, and 96.3%, respectively. None of the patients with either Gleason score <8 or with intermediate risk profile had relapsed. The number of HDR-BT treatments was not related to outcome. Despite of age (median, 65.7 years; range, 45.7-77 years) and considerable pretreatment comorbidity in 39 of 275 patients, Genitourinary treatment-related morbidity was moderate with long-lasting Radiation Therapy Oncology Group Grade 2 voiding problems in 26 patients (9.5%) and occasionally mucous discharge in 20 patients (7%), none with Grade >2 for gastrointestinal at follow-up. Complications during implantations were related to pubic arch interference (4 patients) and lithotomy time, causing 2 patients to develop compartment syndrome. Conclusion: Despite still preliminary observations, our 5-year outcome estimates favor the implementation of high-dose-rate brachytherapy in high-risk patients combined with conformal

  9. National Trends and Predictors of Androgen Deprivation Therapy Use in Low-Risk Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Yang, David D. [Harvard Medical School, Boston, Massachusetts (United States); Muralidhar, Vinayak [Department of Medicine, Harvard Medical School, Boston, Massachusetts (United States); Brigham and Women' s Hospital, Boston, Massachusetts (United States); Mahal, Brandon A. [Harvard Radiation Oncology Program, Boston, Massachusetts (United States); Labe, Shelby A.; Nezolosky, Michelle D.; Vastola, Marie E.; King, Martin T.; Martin, Neil E.; Orio, Peter F. [Department of Radiation Oncology, Harvard Medical School, Boston, Massachusetts (United States); Dana-Farber Cancer Institute, Boston, Massachusetts (United States); Brigham and Women' s Hospital, Boston, Massachusetts (United States); Choueiri, Toni K. [Department of Medical Oncology, Harvard Medical School, Boston, Massachusetts (United States); Dana-Farber Cancer Institute, Boston, Massachusetts (United States); Brigham and Women' s Hospital, Boston, Massachusetts (United States); Trinh, Quoc-Dien [Division of Urological Surgery, Harvard Medical School, Boston, Massachusetts (United States); Brigham and Women' s Hospital, Boston, Massachusetts (United States); Spratt, Daniel E. [Department of Radiation Oncology, Harvard Medical School, Boston, Massachusetts (United States); University of Michigan, Ann Arbor, Michigan (United States); Hoffman, Karen E. [Department of Radiation Oncology, Harvard Medical School, Boston, Massachusetts (United States); The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Feng, Felix Y. [Department of Radiation Oncology, Harvard Medical School, Boston, Massachusetts (United States); Departments of Urology & Medicine and Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California (United States); and others

    2017-06-01

    Purpose: Androgen deprivation therapy (ADT) is not recommended for low-risk prostate cancer because of its lack of benefit and potential for harm. We evaluated the incidence and predictors of ADT use in low-risk disease. Methods and Materials: Using the National Cancer Database, we identified 197,957 patients with low-risk prostate cancer (Gleason score of 3 + 3 = 6, prostate-specific antigen level <10 ng/mL, and cT1-T2a) diagnosed from 2004 to 2012 with complete demographic and treatment information. We used multiple logistic regression to evaluate predictors of ADT use and Cox regression to examine its association with all-cause mortality. Results: Overall ADT use decreased from 17.6% in 2004 to 3.5% in 2012. In 2012, 11.5% of low-risk brachytherapy patients and 7.6% of external beam radiation therapy patients received ADT. Among 82,352 irradiation-managed patients, predictors of ADT use included treatment in a community versus academic cancer program (adjusted odds ratio [AOR], 1.60; 95% confidence interval [CI], 1.50-1.71; P<.001; incidence, 14.0% vs 6.0% in 2012); treatment in the South (AOR, 1.51), Midwest (AOR, 1.81), or Northeast (AOR, 1.90) versus West (P<.001); and brachytherapy use versus external beam radiation therapy (AOR, 1.32; 95% CI, 1.27-1.37; P<.001). Among 25,196 patients who did not receive local therapy, predictors of primary ADT use included a Charlson-Deyo comorbidity score of ≥2 versus 0 (AOR, 1.42; 95% CI, 1.06-1.91; P=.018); treatment in a community versus academic cancer program (AOR, 1.61; 95% CI, 1.37-1.90; P<.001); and treatment in the South (AOR, 1.26), Midwest (AOR, 1.52), or Northeast (AOR, 1.28) versus West (P≤.008). Primary ADT use was associated with increased all-cause mortality in patients who did not receive local therapy (adjusted hazard ratio, 1.28; 95% CI, 1.14-1.43; P<.001) after adjustment for age and comorbidity. Conclusions: ADT use in low-risk prostate cancer has declined nationally but may remain an issue

  10. Posttreatment Prostate-Specific Antigen 6 Months After Radiation With Androgen Deprivation Therapy Predicts for Distant Metastasis–Free Survival and Prostate Cancer–Specific Mortality

    Energy Technology Data Exchange (ETDEWEB)

    Naik, Mihir, E-mail: naikm@ccf.org [Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio (United States); Reddy, Chandana A.; Stephans, Kevin L.; Ciezki, Jay P. [Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio (United States); Garcia, Jorge; Grivas, Petros [Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio (United States); Stephenson, Andrew J.; Klein, Eric A. [Department of Urology, Glickman Urology and Kidney Institute, Cleveland Clinic, Cleveland, Ohio (United States); Tendulkar, Rahul D. [Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio (United States)

    2016-11-01

    Objectives/Background: To determine whether a 6-month posttreatment prostate-specific antigen (PSA) value in patients with prostate cancer (PCa) treated with concurrent androgen deprivation therapy (ADT) and external beam radiation therapy (EBRT) serves as an early predictor for biochemical relapse free survival (bRFS), distant metastasis–free survival (DMFS), and prostate cancer–specific mortality (PCSM). Methods: A retrospective review of intermediate-risk and high-risk PCa patients treated with EBRT and concurrent ADT at a single institution between 1996 and 2012. All patients received high-dose radiation with either 78 Gy in 39 fractions or 70 Gy in 28 fractions. Kaplan-Meier analysis was used to estimate bRFS and DMFS, and cumulative incidence was used to estimate PCSM. Results: 532 patients were identified. The median follow-up time was 7.5 years (range, 1-16.25 years). The median initial PSA (iPSA) was 13.0 ng/mL (range, 0.37-255 ng/mL), and the median duration of ADT was 6 months (range, 1-78 months). The median PSA 6 months after EBRT was 0.1 ng/mL (range, 0-19 ng/mL), and 310 patients (58.3%) had a 6-month PSA ≤0.1 ng/mL. Multivariable analysis (MVA) demonstrated that a 6-month post-EBRT PSA of >0.1 ng/mL was an independent predictor of worse bRFS (hazard ratio [HR] = 2.518; P<.0001), DMFS (HR=3.743; P<.0001), and PCSM (HR=5.435; P<.0001). On MVA, a Gleason score of 8 to 10 also correlated with worse DMFS and PCSM (P<.05). The duration of ADT (1-6 vs >6 months) was not predictive of any clinical endpoint. Conclusions: A 6-month posttreatment PSA >0.1 ng/mL in intermediate-risk and high-risk PCa patients treated with concurrent high-dose EBRT and ADT is associated with worse bRFS, DMFS, and PCSM. The duration of ADT was not predictive of any clinical endpoint. A 6-month PSA after definitive EBRT and ADT helps identify patients at higher risk of disease progression and may serve as a predictive tool to select patients for early

  11. Acceptability of short term neo-adjuvant androgen deprivation in patients with locally advanced prostate cancer

    International Nuclear Information System (INIS)

    Lamb, David S.; Denham, James W.; Mameghan, Hedy; Joseph, David; Turner, Sandra; Matthews, John; Franklin, Ian; Atkinson, Chris; North, John; Poulsen, Michael; Kovacev, Olga; Robertson, Randall; Francis, Lynne; Christie, David; Spry, Nigel A.; Tai, K.-H.; Wynne, Chris; Duchesne, Gillian

    2003-01-01

    Purpose: To determine the acceptability of short term neo-adjuvant maximal androgen deprivation (MAD) to patients treated with external beam radiation for locally advanced prostate cancer. Methods: Between 1996 and 2000, 818 patients with locally advanced, but non-metastatic, prostate cancer were entered into a randomised clinical trial (TROG 96.01), which compared radiation treatment alone with the same radiation treatment and 3 or 6 months neo-adjuvant MAD with goserelin and flutamide. Relevant symptoms, and how troublesome they were to the patient, were scored using a self-assessment questionnaire. This was completed by the patient at registration, and at specified times during and after treatment. Patients taking flutamide had liver function tests checked at regular intervals. Results: All patients have completed at least 12 months follow-up after treatment. Nearly all patients completed planned treatment with goserelin, but 27% of patients in the 6-month MAD treatment arm, and 20% in the 3-month arm, had to stop flutamide early. This was mainly due to altered liver function (up to 17% patients) and bowel side effects (up to 8% patients). However, although flutamide resulted in more bowel symptoms for patients on MAD, there was significant reduction in some urinary symptoms on this treatment. Acute bowel and urinary side effects at the end of radiation treatment were similar in all treatment arms. Side effect severity was unrelated to radiation target volume size, which was reduced by MAD, but symptomatology prior to any treatment was a powerful predictor. Of the 36% of patients who were sexually active before any treatment, the majority became inactive whilst on MAD. However, sexual activity at 12 months after radiation treatment was similar in all treatment arms, indicating that the effects of short term MAD on sexual function are reversible. Conclusion: Despite temporary effects on sexual activity, and compliance difficulties with flutamide, short-term neo

  12. A Small Molecule Polyamine Oxidase Inhibitor Blocks Androgen-Induced Oxidative Stress and Delays Prostate Cancer Progression in the TRAMP Mouse Model

    Science.gov (United States)

    Basu, Hirak S.; Thompson, Todd A.; Church, Dawn R.; Clower, Cynthia C.; Mehraein-Ghomi, Farideh; Amlong, Corey A.; Martin, Christopher T.; Woster, Patrick M.; Lindstrom, Mary J.; Wilding, George

    2009-01-01

    High levels of reactive oxygen species (ROS) present in human prostate epithelia are an important etiological factor in prostate cancer (CaP) occurrence, recurrence and progression. Androgen induces ROS production in the prostate by a yet unknown mechanism. Here, to the best of our knowledge, we report for the first time that androgen induces an overexpression of spermidine/spermine N1-acetyltransferase (SSAT), the rate-limiting enzyme in the polyamine oxidation pathway. As prostatic epithelia produce a large excess of polyamines, the androgen-induced polyamine oxidation that produces H2O2 could be a major reason for the high ROS levels in the prostate epithelia. A small molecule polyamine oxidase inhibitor N,N'-butanedienyl butanediamine (MDL 72,527 or CPC-200) effectively blocks androgen-induced ROS production in human CaP cells as well as significantly delays CaP progression and death in animals developing spontaneous CaP. These data demonstrate that polyamine oxidation is not only a major pathway for ROS production in prostate, but inhibiting this pathway also successfully delays prostate cancer progression. PMID:19773450

  13. Clinical outcomes and nadir prostate-specific antigen (PSA) according to initial PSA levels in primary androgen deprivation therapy for metastatic prostate cancer.

    Science.gov (United States)

    Kitagawa, Yasuhide; Ueno, Satoru; Izumi, Kouji; Kadono, Yoshifumi; Mizokami, Atsushi; Hinotsu, Shiro; Akaza, Hideyuki; Namiki, Mikio

    2016-03-01

    To investigate the clinical outcomes of metastatic prostate cancer patients and the relationship between nadir prostate-specific antigen (PSA) levels and different types of primary androgen deprivation therapy (PADT). This study utilized data from the Japan Study Group of Prostate Cancer registry, which is a large, multicenter, population-based database. A total of 2982 patients treated with PADT were enrolled. Kaplan-Meier analysis was used to compare progression-free survival (PFS) and overall survival (OS) in patients treated using combined androgen blockade (CAB) and non-CAB therapies. The relationships between nadir PSA levels and PADT type according to initial serum PSA levels were also investigated. Among the 2982 enrolled patients, 2101 (70.5 %) were treated with CAB. Although CAB-treated patients had worse clinical characteristics, their probability of PFS and OS was higher compared with those treated with a non-CAB therapy. These results were due to a survival benefit with CAB in patients with an initial PSA level of 500-1000 ng/mL. Nadir PSA levels were significantly lower in CAB patients than in non-CAB patients with comparable initial serum PSA levels. A small survival benefit for CAB in metastatic prostate cancer was demonstrated in a Japanese large-scale prospective cohort study. The clinical significance of nadir PSA levels following PADT was evident, but the predictive impact of PSA nadir on OS was different between CAB and non-CAB therapy.

  14. Splicing Factor Prp8 Interacts With NES(AR) and Regulates Androgen Receptor in Prostate Cancer Cells.

    Science.gov (United States)

    Wang, Dan; Nguyen, Minh M; Masoodi, Khalid Z; Singh, Prabhpreet; Jing, Yifeng; O'Malley, Katherine; Dar, Javid A; Dhir, Rajiv; Wang, Zhou

    2015-12-01

    Androgen receptor (AR) plays a pivotal role in the development of primary as well as advanced castration-resistant prostate cancer. Previous work in our lab identified a novel nuclear export signal (NES) (NES(AR)) in AR ligand-binding domain essential for AR nucleocytoplasmic trafficking. By characterizing the localization of green fluorescence protein (GFP)-tagged NES(AR), we designed and executed a yeast mutagenesis screen and isolated 7 yeast mutants that failed to display the NES(AR) export function. One of those mutants was identified as the splicing factor pre-mRNA processing factor 8 (Prp8). We further showed that Prp8 could regulate NES(AR) function using short hairpin RNA knockdown of Prp8 coupled with a rapamycin export assay in mammalian cells and knockdown of Prp8 could induce nuclear accumulation of GFP-tagged AR in PC3 cells. Prp8 expression was decreased in castration-resistant LuCaP35 xenograft tumors as compared with androgen-sensitive xenografts. Laser capture microdissection and quantitative PCR showed Prp8 mRNA levels were decreased in human prostate cancer specimens with high Gleason scores. In prostate cancer cells, coimmunoprecipitation and deletion mutagenesis revealed a physical interaction between Prp8 and AR mainly mediated by NES(AR). Luciferase assay with prostate specific antigen promoter-driven reporter demonstrated that Prp8 regulated AR transcription activity in prostate cancer cells. Interestingly, Prp8 knockdown also increased polyubiquitination of endogenous AR. This may be 1 possible mechanism by which it modulates AR activity. These results show that Prp8 is a novel AR cofactor that interacts with NES(AR) and regulates AR function in prostate cancer cells.

  15. [Histopathological changes due to transurethural microwave thermotherapy associated with androgen deprivation therapy in patients with localized prostate cancer].

    Science.gov (United States)

    Jujo, Yutaka; Koshiba, Ken; Suzuki, Ryuta; Hoshiai, Osamu; Endo, Tadao; Aihara, Masahiro; Katsuta, Masayuki; Nakajo, Hirotaka

    2006-03-01

    The 2nd generation transurethral microwave thermotherapy (TUMT), equipped with high energy microwave generator and urethral cooling device is widely accepted as an less invasive effective modality to treat benign prostatic hyperplasia. For prostatic cancer, however, it is generally estimated as insufficient because of limitation in penetration of microwave into deep prostatic tissue. In this study, we examined histopathologic changes after androgen deprivation theraphy (ADT) and TUMT. Ten patients with localized prostate cancer underwent ADT for 3 months, and then TUMT was proceeded using Urowave (Dornier MedTech GmbH). Additional 3 months after TUMT and continued ADT, TURP in radical fashion was performed in all the patients, and all the resected chips were submitted for pathological study. Significant reduction in prostate volume was noted after NHT for 3 months from 37.4 +/- 9.6 ml to 22.0 +/- 5.6 ml. The pathological study of resected chips revealed progressive fibrotic changes without viable cancer cells in 9 of 10 patients. In 1 patient, however, some remnant of carcinomatous foci were noted in a resected chip from the middle lobe of the prostate. Although the number of patient is limited and longer follow-up is needed, the results in present series was interested and worth considering.

  16. QUANTITATIVE STUDIES OF PROSTATIC SECRETION : I. CHARACTERISTICS OF THE NORMAL SECRETION; THE INFLUENCE OF THYROID, SUPRARENAL, AND TESTIS EXTIRPATION AND ANDROGEN SUBSTITUTION ON THE PROSTATIC OUTPUT.

    Science.gov (United States)

    Huggins, C; Masina, M H; Eichelberger, L; Wharton, J D

    1939-11-30

    A simple isolation of the prostate enabled quantitative collection of prostatic secretion in dogs over periods of months. The secretory stimulant was pilocarpine and 2 similar amounts injected with a 6 hour interval gave smaller amounts at the second testing, suggesting a fatigue effect. The prostate was not absolutely refractory since doubling the amount of alkaloid injected at the second test increased the volume to equal or exceed the preliminary secretion. The depression effect had disappeared at 24 hours. In normal dogs the secretory curves were essentially regular, with occasional prolonged rises or depressions. The amount of secretion did not bear a direct relationship to the weight of the gland in adult dogs. The germinal epithelium of the testis underwent atrophy during the first few weeks of cage life while the prostatic secretion was maintained, showing that the atrophy was differential and did not involve the cells producing the androgenic hormone. The atrophy was reversible and all dogs kept for more than 4 months showed restoration of the germ cells. A few dogs developed atrophy of the germinal cells with cessation of prostatic secretion for many weeks but with final recovery. Removal of the suprarenal glands with suprarenal insufficiency did not produce sterility. The distribution of electrolytes in the prostatic secretion differed from that in the serum-transudate system, although the concentration of osmotically active substances was the same, being made up almost entirely of sodium and chloride. The distribution was not affected by the different physiological procedures used in this study. Protein concentrations were less than 1 per cent. The rate of prostatic atrophy following castration was determined, and cessation of secretion occurred in 7 to 23 days. The restoration of prostatic fluid in castrate dogs following daily injections of testosterone propionate followed a smooth curve to form a plateau which was interrupted occasionally by

  17. Effects of Androgen Blockade on Cognitive Function and Quality of Life in Men with Prostate Cancer

    National Research Council Canada - National Science Library

    Grigsby, James

    2004-01-01

    .... Our major hypothesis is the patients undergoing androgen deprivation therapy will experience impairments in those cognitive abilities reported in the research literature to be related to androgen levels (e.g...

  18. Effects of Androgen Blockade on Cognitive Function and Quality of Life in Men with Prostate Cancer

    National Research Council Canada - National Science Library

    Grigaby, James

    2003-01-01

    .... Our major hypothesis is that patients undergoing androgen deprivation therapy will experience impairments in those cognitive abilities reported in the research literature to be related to androgen levels (e.g...

  19. Obesity and the Odds of Weight Gain following Androgen Deprivation Therapy for Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Lior Z. Braunstein

    2014-01-01

    Full Text Available Background. Increasing body mass index (BMI is associated with increased risk of mortality; however, quantifying weight gain in men undergoing androgen deprivation therapy (ADT for prostate cancer (PC remains unexplored. Methods. Between 1995 and 2001, 206 men were enrolled in a randomized trial evaluating the survival difference of adding 6 months of ADT to radiation therapy (RT. BMI measurements were available in 171 men comprising the study cohort. The primary endpoint was weight gain of ≥10 lbs by 6-month followup. Logistic regression analysis was performed to assess whether baseline BMI or treatment received was associated with this endpoint adjusting for known prognostic factors. Results. By the 6-month followup, 12 men gained ≥10 lbs, of which 10 (83% received RT + ADT and, of these, 7 (70% were obese at randomization. Men treated with RT as compared to RT + ADT were less likely to gain ≥10 lbs (adjusted odds ratio (AOR: 0.18 [95% CI: 0.04–0.89]; P=0.04, whereas this risk increased with increasing BMI (AOR: 1.15 [95% CI: 1.01–1.31]; P=0.04. Conclusions. Consideration should be given to avoid ADT in obese men with low- or favorable-intermediate risk PC where improved cancer control has not been observed, but shortened life expectancy from weight gain is expected.

  20. Cardiometabolic and Skeletal Risk Factors in Black Men with Prostate Cancer Starting Androgen Deprivation Therapy

    International Nuclear Information System (INIS)

    Gunnarsson, Orvar; Basaria, Shehzad; Gignac, Gretchen A.

    2015-01-01

    Background: Androgen deprivation therapy (ADT) for prostate cancer (PCa) is associated with multiple metabolic complications, previously predominantly evaluated in the white population. Methods: A chart-based retrospective review was conducted on black patients with PCa, considered for ADT, from September 2007 to July 2010. Baseline data were collected on body mass index (BMI), vitamin-D status, bone mineral density (BMD), dyslipidemia and diabetes. Overweight and obesity were classified as BMI ≥ 25 and BMI ≥ 30, respectively. Vitamin-D sufficiency was defined as levels ≥30 ng/mL, insufficiency as <30 ng/mL and deficiency as ≤20 ng/mL. Osteopenia was defined as T scores between −1 to −2.5 and osteoporosis when T scores ≤−2.5. Results: Of the initial cohort of 130 black men, 111 (85.4%) patients underwent ADT. At baseline, average BMI was 28.1 ± 5.9 with 43.3% of men being overweight and 30.8% obese. More than one-third of the patients had pre-existing dyslipidemia while 28.8% were diabetics. 50% were vitamin-D deficient while 41% had low bone mass. Conclusions: Black men with PCa presenting for consideration of ADT have a high prevalence of existing metabolic risk factors. Close monitoring of this patient population is needed during ADT to prevent and treat metabolic complications

  1. Clinical Relevance of Androgen Receptor Splice Variants in Castration-Resistant Prostate Cancer.

    Science.gov (United States)

    Maughan, Benjamin L; Antonarakis, Emmanuel S

    2015-12-01

    Metastatic castration-resistant prostate cancer (mCRPC) currently benefits from a wealth of treatment options, yet still remains lethal in the vast majority of patients. It is becoming increasingly understood that this disease entity continues to evolve over time, acquiring additional and diverse resistance mechanisms with each subsequent therapy used. This dynamic relationship between treatment pressure and disease resistance can be challenging for the managing clinician. The recent discovery of alternate splice variants of the androgen receptor (AR) is one potential mechanism of escape in mCRPC, and recognizing this resistance mechanism might be important for optimal treatment selection for our patients. AR-V7 appears to be the most relevant AR splice variant, and early clinical data suggest that it is a negative prognostic marker in mCRPC. Emerging evidence also suggests that detection of AR-V7 may be associated with resistance to novel hormonal therapy (abiraterone and enzalutamide) but may be compatible with sensitivity to taxane chemotherapy (docetaxel and cabazitaxel). Adding to this complexity is the observation that AR-V7 is a dynamic marker whose status may change across time and depending on selective pressures induced by different therapies. Finally, it is possible that AR-V7 may represent a therapeutic target in mCRPC if drugs can be designed that degrade or inhibit AR splice variants or block their transcriptional activity. Several such agents (including galeterone, EPI-506, and bromodomain/BET inhibitors) are now in clinical development.

  2. Cardiometabolic and Skeletal Risk Factors in Black Men with Prostate Cancer Starting Androgen Deprivation Therapy

    Directory of Open Access Journals (Sweden)

    Orvar Gunnarsson

    2015-04-01

    Full Text Available Background: Androgen deprivation therapy (ADT for prostate cancer (PCa is associated with multiple metabolic complications, previously predominantly evaluated in the white population. Methods: A chart-based retrospective review was conducted on black patients with PCa, considered for ADT, from September 2007 to July 2010. Baseline data were collected on body mass index (BMI, vitamin-D status, bone mineral density (BMD, dyslipidemia and diabetes. Overweight and obesity were classified as BMI ≥ 25 and BMI ≥ 30, respectively. Vitamin-D sufficiency was defined as levels ≥30 ng/mL, insufficiency as <30 ng/mL and deficiency as ≤20 ng/mL. Osteopenia was defined as T scores between −1 to −2.5 and osteoporosis when T scores ≤−2.5. Results: Of the initial cohort of 130 black men, 111 (85.4% patients underwent ADT. At baseline, average BMI was 28.1 ± 5.9 with 43.3% of men being overweight and 30.8% obese. More than one-third of the patients had pre-existing dyslipidemia while 28.8% were diabetics. 50% were vitamin-D deficient while 41% had low bone mass. Conclusions: Black men with PCa presenting for consideration of ADT have a high prevalence of existing metabolic risk factors. Close monitoring of this patient population is needed during ADT to prevent and treat metabolic complications.

  3. Cardiometabolic and Skeletal Risk Factors in Black Men with Prostate Cancer Starting Androgen Deprivation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Gunnarsson, Orvar, E-mail: orvar.gunnarsson@uphs.upenn.edu [Department of Medicine, Division of Hematology and Oncology, Hospital of the University of Pennsylvania, 3400 Spruce Street, 16 Penn Tower, Philadelphia, PA 19104 (United States); Basaria, Shehzad [Department of Medicine, Section of Men’s Health, Aging and Metabolism, Brigham and Women’s Hospital, Boston, MA 02115 (United States); Gignac, Gretchen A. [Department of Medicine, Section of Hematology and Oncology, Boston University School of Medicine, Boston, MA 02118 (United States)

    2015-04-22

    Background: Androgen deprivation therapy (ADT) for prostate cancer (PCa) is associated with multiple metabolic complications, previously predominantly evaluated in the white population. Methods: A chart-based retrospective review was conducted on black patients with PCa, considered for ADT, from September 2007 to July 2010. Baseline data were collected on body mass index (BMI), vitamin-D status, bone mineral density (BMD), dyslipidemia and diabetes. Overweight and obesity were classified as BMI ≥ 25 and BMI ≥ 30, respectively. Vitamin-D sufficiency was defined as levels ≥30 ng/mL, insufficiency as <30 ng/mL and deficiency as ≤20 ng/mL. Osteopenia was defined as T scores between −1 to −2.5 and osteoporosis when T scores ≤−2.5. Results: Of the initial cohort of 130 black men, 111 (85.4%) patients underwent ADT. At baseline, average BMI was 28.1 ± 5.9 with 43.3% of men being overweight and 30.8% obese. More than one-third of the patients had pre-existing dyslipidemia while 28.8% were diabetics. 50% were vitamin-D deficient while 41% had low bone mass. Conclusions: Black men with PCa presenting for consideration of ADT have a high prevalence of existing metabolic risk factors. Close monitoring of this patient population is needed during ADT to prevent and treat metabolic complications.

  4. Metabolic syndrome in patients with prostate cancer undergoing intermittent androgen-deprivation therapy.

    Science.gov (United States)

    Rezaei, Mohammadali Mohammadzadeh; Rezaei, Mohammadhadi Mohammadzadeh; Ghoreifi, Alireza; Kerigh, Behzad Feyzzadeh

    2016-01-01

    The presence of metabolic syndrome in men with prostate cancer (PCa) undergoing androgen-deprivation therapy (ADT), especially intermittent type, has not been completely evaluated. The aim of this study is to evaluate metabolic syndrome in men with PCa undergoing intermittent ADT. In this longitudinal study, we studied the prevalence of metabolic syndrome and its components in 190 patients who were undergoing intermittent ADT. The metabolic syndrome was defined according to the Adult Treatment Panel III criteria. All metabolic parameters, including lipid profile, blood glucose, blood pressures, and waist circumferences of the patients were measured six and 12 months after treatment. Mean age of the patients was 67.5 ± 6.74 years. The incidence of metabolic syndrome after six and 12 months was 6.8% and 14.7%, respectively. Analysis of various components of the metabolic syndrome revealed that patients had significantly higher overall prevalence of hyperglycemia, abdominal obesity, and hypertriglyceridemia in their six- and 12-month followups, but blood pressure has not been changed in the same period except for diastolic blood pressure after six months. Although there was an increased risk of metabolic syndrome in patients receiving intermittent ADT, it was lower than other studies that treated the same patients with continuous ADT. Also it seems that intermittent ADT has less metabolic complications than continuous ADT and could be used as a safe alternative in patients with advanced and metastatic PCa.

  5. Androgen Receptor-Mediated Growth Suppression of HPr-1AR and PC3-Lenti-AR Prostate Epithelial Cells.

    Directory of Open Access Journals (Sweden)

    Young-Chae Kim

    Full Text Available The androgen receptor (AR mediates the developmental, physiologic, and pathologic effects of androgens including 5α-dihydrotestosterone (DHT. However, the mechanisms whereby AR regulates growth suppression and differentiation of luminal epithelial cells in the prostate gland and proliferation of malignant versions of these cells are not well understood, though they are central to prostate development, homeostasis, and neoplasia. Here, we identify androgen-responsive genes that restrain cell cycle progression and proliferation of human prostate epithelial cell lines (HPr-1AR and PC3-Lenti-AR, and we investigate the mechanisms through which AR regulates their expression. DHT inhibited proliferation of HPr-1AR and PC3-Lenti-AR, and cell cycle analysis revealed a prolonged G1 interval. In the cell cycle, the G1/S-phase transition is initiated by the activity of cyclin D and cyclin-dependent kinase (CDK complexes, which relieve growth suppression. In HPr-1AR, cyclin D1/2 and CDK4/6 mRNAs were androgen-repressed, whereas CDK inhibitor, CDKN1A, mRNA was androgen-induced. The regulation of these transcripts was AR-dependent, and involved multiple mechanisms. Similar AR-mediated down-regulation of CDK4/6 mRNAs and up-regulation of CDKN1A mRNA occurred in PC3-Lenti-AR. Further, CDK4/6 overexpression suppressed DHT-inhibited cell cycle progression and proliferation of HPr-1AR and PC3-Lenti-AR, whereas CDKN1A overexpression induced cell cycle arrest. We therefore propose that AR-mediated growth suppression of HPr-1AR involves cyclin D1 mRNA decay, transcriptional repression of cyclin D2 and CDK4/6, and transcriptional activation of CDKN1A, which serve to decrease CDK4/6 activity. AR-mediated inhibition of PC3-Lenti-AR proliferation occurs through a similar mechanism, albeit without down-regulation of cyclin D. Our findings provide insight into AR-mediated regulation of prostate epithelial cell proliferation.

  6. Bipolar Androgen Therapy for Men With Androgen Ablation Naïve Prostate Cancer: Results From the Phase II BATMAN Study.

    Science.gov (United States)

    Schweizer, Michael T; Wang, Hao; Luber, Brandon; Nadal, Rosa; Spitz, Avery; Rosen, D Marc; Cao, Haiyi; Antonarakis, Emmanuel S; Eisenberger, Mario A; Carducci, Michael A; Paller, Channing; Denmeade, Samuel R

    2016-09-01

    We have previously documented a paradoxical anti-tumor effect when castration-resistant prostate cancer patients were treated with intermittent, high-dose testosterone (i.e., Bipolar Androgen Therapy; BAT). Because, an adaptive increase in androgen receptor expression following chronic androgen deprivation therapy (ADT) may underlie this effect, we tested whether men with hormone-sensitive (HS) prostate cancer (PC) would also respond to BAT if given following a 6-month ADT lead-in. Asymptomatic HS PC patients with low metastatic burden or non-metastatic biochemically recurrent disease were enrolled. Following 6-month of ADT, those with a PSA <4 ng/ml went on to receive alternating 3-month cycles of BAT and ADT. BAT was administered as intramuscular testosterone (T) cypionate or enanthate 400 mg on Days (D) 1, 29, and 57. ADT was continued throughout the study to allow rapid cycling from near castrate to supraphysiologic range T following T injections. The primary endpoint was the percent of patients with a PSA <4 ng/ml after 18 months. Secondary endpoints included radiographic response and quality of life (QoL). Twenty-nine of 33 patients received BAT following the ADT lead-in. The primary endpoint was met, with 17/29 men (59%, 90% confidence interval: 42-74%) having a PSA <4 ng/ml at 18 months. Ten patients receiving BAT had RECIST evaluable disease, and eight (80%) objective responses were observed (four complete; four partial). Three patients progressed per RECIST criteria and three had unconfirmed progression on bone scan. Men treated with 6-month of ADT had improved QoL following the first cycle of BAT as measured by the SF-36, FACT-P, and IIEF surveys. BAT demonstrated preliminary efficacy in men with HS PC following 6-month of ADT. BAT may improve QoL in men treated with ADT. Prostate 76:1218-1226, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  7. Prepubertal adrenarchal androgens and animal protein intake independently and differentially influence pubertal timing.

    Science.gov (United States)

    Remer, Thomas; Shi, Lijie; Buyken, Anette E; Maser-Gluth, Christiane; Hartmann, Michaela F; Wudy, Stefan A

    2010-06-01

    Whether adrenarche impacts on pubertal development is controversial. The objective of the study was to examine the associations of adrenal androgen (AA) secretion with early and late pubertal markers, independent of potential influences of dietary animal protein intake. This was a prospective cohort study of healthy free-living Caucasian children (n = 109) who provided both 24-h urine samples and 3-d weighed dietary records 1 and 2 yr before the biological age at take-off of the pubertal growth spurt (ATO). Twenty-four-hour excretion rates of androgen (C19) metabolites quantified by gas chromatography-mass spectrometry were measured. ATO, age at peak height velocity (APHV), age at menarche/voice break, duration of pubertal growth acceleration, and ages at Tanner stage 2 for breast (girls) and genital (boys) development (B2-G2) and pubic hair (PH2). Higher adrenarchal C19 steroids predicted earlier ages at Tanner stage 2 for pubic hair (P voice break (P = 0.07). A higher animal protein intake may be involved in an earlier attainment of ATO and APHV, whereas a more intensive adrenarchal process may precipitate a shorter pubertal growth spurt and a notably earlier onset of breast and genital development in girls and boys, respectively.

  8. Inhibition of Androgen Receptor Nuclear Localization and Castration-Resistant Prostate Tumor Growth by Pyrroloimidazole-based Small Molecules.

    Science.gov (United States)

    Masoodi, Khalid Z; Xu, Yadong; Dar, Javid A; Eisermann, Kurtis; Pascal, Laura E; Parrinello, Erica; Ai, Junkui; Johnston, Paul A; Nelson, Joel B; Wipf, Peter; Wang, Zhou

    2017-10-01

    The androgen receptor (AR) is a ligand-dependent transcription factor that controls the expression of androgen-responsive genes. A key step in androgen action, which is amplified in castration-resistant prostate cancer (CRPC), is AR nuclear translocation. Small molecules capable of inhibiting AR nuclear localization could be developed as novel therapeutics for CRPC. We developed a high-throughput screen and identified two structurally-related pyrroloimidazoles that could block AR nuclear localization in CRPC cells. We show that these two small molecules, 3-(4-ethoxyphenyl)-6,7-dihydro-5 H -pyrrolo[1,2- a ]imidazole (EPPI) and 3-(4-chlorophenyl)-6,7-dihydro-5 H -pyrrolo[1,2- a ]imidazole (CPPI) can inhibit the nuclear localization and transcriptional activity of AR and reduce the proliferation of AR-positive but not AR-negative prostate cancer cell lines. EPPI and CPPI did not inhibit nuclear localization of the glucocorticoid receptor or the estrogen receptor, suggesting they selectively target AR. In LNCaP tumor xenografts, CPPI inhibited the proliferation of relapsed LNCaP tumors. These findings suggest that EPPI and CPPI could serve as lead structures for the development of therapeutic agents for CRPC. Mol Cancer Ther; 16(10); 2120-9. ©2017 AACR . ©2017 American Association for Cancer Research.

  9. Total glucosides of paeony inhibits lipopolysaccharide-induced proliferation, migration and invasion in androgen insensitive prostate cancer cells.

    Directory of Open Access Journals (Sweden)

    Zhi-Hui Zhang

    Full Text Available Previous studies demonstrated that inflammatory microenvironment promoted prostate cancer progression. This study investigated whether total glucosides of paeony (TGP, the active constituents extracted from the root of Paeonia Lactiflora Pall, suppressed lipopolysaccharide (LPS-stimulated proliferation, migration and invasion in androgen insensitive prostate cancer cells. PC-3 cells were incubated with LPS (2.0 μg/mL in the absence or presence of TGP (312.5 μg /mL. As expected, cells at S phase and nuclear CyclinD1, the markers of cell proliferation, were increased in LPS-stimulated PC-3 cells. Migration activity, as determined by wound-healing assay and transwell migration assay, and invasion activity, as determined by transwell invasion assay, were elevated in LPS-stimulated PC-3 cells. Interestingly, TGP suppressed LPS-stimulated PC-3 cells proliferation. Moreover, TGP inhibited LPS-stimulated migration and invasion of PC-3 cells. Additional experiment showed that TGP inhibited activation of nuclear factor kappa B (NF-κB and mitogen-activated protein kinase (MAPK/p38 in LPS-stimulated PC-3 cells. Correspondingly, TGP attenuated upregulation of interleukin (IL-6 and IL-8 in LPS-stimulated PC-3 cells. In addition, TGP inhibited nuclear translocation of signal transducer and activator of transcription 3 (STAT3 in LPS-stimulated PC-3 cells. These results suggest that TGP inhibits inflammation-associated STAT3 activation and proliferation, migration and invasion in androgen insensitive prostate cancer cells.

  10. Factors associated with the omission of androgen deprivation therapy in radiation-managed high-risk prostate cancer.

    Science.gov (United States)

    Chen, Yu-Wei; Muralidhar, Vinayak; Mahal, Brandon A; Nezolosky, Michelle D; Beard, Clair J; Choueiri, Toni K; Hoffman, Karen E; Martin, Neil E; Orio, Peter F; Sweeney, Christopher J; Feng, Felix Y; Trinh, Quoc-Dien; Nguyen, Paul L

    Androgen deprivation therapy (ADT) has been shown to improve survival for men with unfavorable-risk prostate cancer (PCa). We investigated the utilization and factors associated with the omission of ADT in radiation-managed high-risk PCa. We used the National Cancer Database to identify men with National Comprehensive Cancer Network high-risk PCa treated with external beam radiation therapy (EBRT) with or without brachytherapy boost from 2004 to 2012. Multivariable logistic regression adjusting for clinical and sociodemographic factors was used to identify independent predictors for ADT use. A total of 57,968 radiation-treated high-risk PCa men were included in our analysis. There were 49,363 patients (85.2%) treated with EBRT alone and 8605 patients (14.8%) treated with EBRT plus brachytherapy boost. Overall, 77% of men received ADT. In multivariable regression analysis, the use of brachytherapy boost was associated with a significantly lower utilization of ADT (70% vs. 78%; adjusted odds ratio [AOR]: 0.65; 95% CI: 0.62-0.69; p-Value use was seen with higher Gleason scores, PSA, and T-category (all p-Values <0.001). Approximately one in four men with radiation-managed high-risk PCa do not receive ADT, which may reflect concerns about its toxicity profile despite known improvements in overall survival. Practice patterns suggest that some providers believe dose escalation through brachytherapy boost may obviate the need for ADT in some high-risk patients, but this hypothesis requires further testing. Copyright © 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

  11. [Clinical Study of 2014 ISUP New Grade Group Classification for Prostate Cancer Patients Treated by Androgen Deprivation Therapy].

    Science.gov (United States)

    Uno, Masahiro; Kawase, Makoto; Kato, Daiki; Ishida, Takashi; Kato, Seiichi; Fujimoto, Yoshinori

    2018-01-01

    The 2014 International Society of Urological Pathology (ISUP) has proposed a new grade group (GG) classification for Gleason scores (GS). The usefulness of the new GG classification was investigated with 518 prostate cancer patients who underwent androgen deprivation therapy. According to the new GG classification, Stages B‒D and the new GG classification relapse-free rate for each stage were calculated using the Kaplan‒Meier method. The new GG classification revealed a significant difference for the relapse-free rate only between some groups. Analysis using the Cox proportional hazards model indicated that the risk of relapse was higher in GGs 4 and 5 than in GG 1. The usefulness about the relapse-free rate in androgen deprivation therapy of the 2014 ISUP new grade group classification a waits future examination.

  12. Adjuvant and salvage therapy following radical prostatectomy for prostate cancer: effect of combined transient androgen deprivation and irradiation

    International Nuclear Information System (INIS)

    Eulau, Stephen M.; Tate, David J.; Cox, Richard S.; Bagshaw, Malcolm A.; Hancock, Steven L.

    1996-01-01

    Purpose: Adjuvant and salvage irradiation have been shown to improve local control after radical prostatectomy for prostatic cancer in patients with high risk pathologic features, rising PSA, or evidence of local failure. Transient androgen deprivation combined with primary irradiation has resulted in improved local control and biochemical disease free survival in patients with locally advanced, unresected, prostate cancer. This retrospective study evaluates whether transient androgen blockade improves the outcome from post-prostatectomy irradiation given as either adjuvant or salvage therapy. Methods: From August, 1985 to December, 1995, 105 patients were treated with radiotherapy to the prostatic fossa following radical prostatectomy for adenocarcinoma of the prostate. No patient had clinically or radiographically evident distant disease. Median follow-up was 4.6 years from the date of surgery and 3.2 years from completion of radiotherapy. Findings at prostatectomy included capsular penetration in 38 patients, seminal vesicle involvement in 42 patients, lymph node involvement in 15 patients, and positive surgical margins in 70 patients. Treatment was administered as adjuvant therapy for high risk pathologic features in 39 patients, for persistent or rising PSA in 52 patients, or for clinically evident local recurrence in 14 patients. Of the 105 patients, 32 received combined androgen deprivation/radiotherapy and 73 received radiotherapy alone. Both groups received 60-70 Gy in 2 Gy daily fractions to the prostatic fossa. Selected patients with poor prognostic features received pelvic irradiation to a median dose of 50 Gy. Androgen deprivation typically consisted of Lupron and Flutamide for 4 to 6 months before, during, and in selected cases, after irradiation. No patients received maintenance androgen deprivation or underwent orchiectomy. Tumor stage, lymph node status, Gleason sum, and indications for treatment did not differ significantly between the two groups

  13. A Prospective Audit of Intermittent Anti-Androgen verses Pituitary Blockade Suggests a Bipolar Androgen Type Strategy May Be Safe in Untreated Prostate Cancer.

    Science.gov (United States)

    Oliver, Timothy; Wilson, Peter; Ansell, Wendy; Philp, Tim; Chinegwundoh, Frank; Shamash, Jonathan; Shaw, Greg; Ahmad, Amar

    2018-01-01

    A locally advanced Gleason 4 + 4 prostate cancer patient who was on self-medication with intermittent anti-androgen monotherapy (iAAm) over 14 years suggested that raised testosterone was not dangerous and this suggestion needed investigating. Others who were on AA continuously were recruited to ongoing audit of intermittent hormone therapy (IHT) and iAAm outcomes were compared with intermittent LHRH therapy (iLHRH or iMAB). Between 1994 and 2007, 111 patients sought IHT because of side effects of treatment. Forty-two M0 patients received IHT with iLHRHm or iMAB and 33 received iAAm (31 of these were M0). PSA nadir below 4 was necessary for entry. Overall survival was 87, 72 and 67% with iAAm and 73, 56 and 43% with iLHRH/MAB at 5, 8 and 10 years respectively. Overall survival was 61, 55 and 33% continued on iAAm and 56, 41, and 32% on iLHRH/MAB at 5, 8, and 10 years respectively. Multivariable analysis and matched case control analysis confirm that the maintenance of advantage for iAAm Testosterone levels in patients on iAAm compared to iLHRH therapy was more intense throughout treatment. These results complement recent progress in using bipolar androgen therapy to reverse castration resistance and add to the increasing acceptance that controlled testosterone exposure might be relevant in hormone-naïve patients. © 2017 S. Karger AG, Basel.

  14. Prostate-specific antigen-activated thapsigargin prodrug as targeted therapy for prostate cancer

    DEFF Research Database (Denmark)

    Denmeade, Samuel R; Jakobsen, Carsten M; Janssen, Samuel

    2003-01-01

    Standard anti-proliferative chemotherapy is relatively ineffective against slowly proliferating androgen-independent prostate cancer cells within metastatic sites. In contrast, the lipophilic cytotoxin thapsigargin, which causes apoptosis by disrupting intracellular free Ca2+ levels, is effective...

  15. Large institutional variations in use of androgen deprivation therapy with definitive radiotherapy in a population-based cohort of men with intermediate- and high-risk prostate cancer.

    Science.gov (United States)

    Ong, Wee Loon; Foroudi, Farshad; Evans, Sue; Millar, Jeremy

    2017-11-01

    To evaluate the pattern of use of androgen deprivation therapy (ADT) with definitive radiotherapy (RT) in men with prostate cancer (PCa) in a population-based study in Australia. This is a prospective cohort of men with intermediate- and high-risk PCa, captured in the population-based Prostate Cancer Outcome Registry Victoria, who were treated with definitive prostate RT between January 2010 and December 2015. The primary outcome of interest was ADT utilization. Chi-squared test for trend was used to evaluate the temporal trend in the use of ADT over the study period. Multivariate logistic regressions were used to evaluate the effects of patient-, tumour- and treatment-related factors, and treatment institutions (public/ private and metropolitan/ regional) on the likelihood of ADT utilization. A total of 1806 men were included in the study, 199 of whom (11%) had favourable National Comprehensive Cancer Network (NCCN) intermediate-risk disease (i.e. only one intermediate-risk feature, primary Gleason grade 3, and use of brachytherapy boost), treatment institution (public and regional) remained independently associated with increased likelihood of ADT utilization. Men with intermediate-risk PCa treated in regional and public institutions were 2.7 times (95% confidence interval [CI] 1.9-3.9; P use of ADT with definitive prostate RT. While there was an increasing trend towards use of ADT over time, ADT still appeared to be underutilized in certain groups of patients who may benefit from ADT, with approximately one in five men with high-risk and one in two with unfavourable intermediate-risk PCa not receiving ADT with RT. There was notable variation in the use of ADT between public vs private and metropolitan vs regional institutions. © 2017 The Authors BJU International © 2017 BJU International Published by John Wiley & Sons Ltd.

  16. Androgen receptor regulated microRNA miR-182-5p promotes prostate cancer progression by targeting the ARRDC3/ITGB4 pathway

    International Nuclear Information System (INIS)

    Yao, Jingjing; Xu, Chen; Fang, Ziyu; Li, Yaoming; Liu, Houqi; Wang, Yue; Xu, Chuanliang; Sun, Yinghao

    2016-01-01

    Abstracts: MicroRNAs (miRNAs) are important endogenous gene regulators that play key roles in prostate cancer development and metastasis. However, specific miRNA expression patterns in prostate cancer tissues from Chinese patients remain largely unknown. In this study, we compared miRNA expression patterns in 65 pairs of prostate cancer and para-cancer tissues by RNA sequencing and found that miR-182-5p was the most up-regulated miRNA in prostate cancer tissues. The result was validated using realtime PCR in 18 pairs of prostate cancer and para-cancer tissues. In in vitro analysis, it was confirmed that miR-182-5p promotes prostate cancer cell proliferation, invasion and migration and inhibit apoptosis. In addition, the androgen receptor directly regulated the transcription of miR-182-5p, which could target to the 3′UTR of ARRDC3 mRNA and affect the expression of ARRDC3 and its downstream gene ITGB4. For the in vivo experiment, miR-182-5p overexpression also promoted the growth and progression of prostate cancer tumors. In this regard, we suggest that miR-182-5p may be a key androgen receptor-regulated factor that contributes to the development and metastasis of Chinese prostate cancers and may be a potential target for the early diagnosis and therapeutic studies of prostate cancer. -- Highlights: •miR-182-5p is the mostly up-regulated miRNA in Chinese prostate cancer. •miR-182-5p is regulated by androgen receptor. •miR-182-5p promotes prostate cancer progression. •miR-182-5p regulates ARRDC3/ITGB4 pathway.

  17. Androgen receptor regulated microRNA miR-182-5p promotes prostate cancer progression by targeting the ARRDC3/ITGB4 pathway

    Energy Technology Data Exchange (ETDEWEB)

    Yao, Jingjing [Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, 200433 (China); Xu, Chen [Research Center of Developmental Biology, Second Military Medical University, 800th Xiangyin Road, Shanghai, 200433 (China); Department of Orthopedics, Changzheng Hospital Affiliated to Second Military Medical University, 415th Feng Yang Road, Shanghai, 200003 (China); Fang, Ziyu; Li, Yaoming [Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, 200433 (China); Liu, Houqi; Wang, Yue [Research Center of Developmental Biology, Second Military Medical University, 800th Xiangyin Road, Shanghai, 200433 (China); Translational Medicine Center, Second Military Medical University, 800th Xiangyin Road, Shanghai, 200433 (China); Xu, Chuanliang [Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, 200433 (China); Sun, Yinghao, E-mail: sunyh@medmail.com.cn [Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, 200433 (China)

    2016-05-20

    Abstracts: MicroRNAs (miRNAs) are important endogenous gene regulators that play key roles in prostate cancer development and metastasis. However, specific miRNA expression patterns in prostate cancer tissues from Chinese patients remain largely unknown. In this study, we compared miRNA expression patterns in 65 pairs of prostate cancer and para-cancer tissues by RNA sequencing and found that miR-182-5p was the most up-regulated miRNA in prostate cancer tissues. The result was validated using realtime PCR in 18 pairs of prostate cancer and para-cancer tissues. In in vitro analysis, it was confirmed that miR-182-5p promotes prostate cancer cell proliferation, invasion and migration and inhibit apoptosis. In addition, the androgen receptor directly regulated the transcription of miR-182-5p, which could target to the 3′UTR of ARRDC3 mRNA and affect the expression of ARRDC3 and its downstream gene ITGB4. For the in vivo experiment, miR-182-5p overexpression also promoted the growth and progression of prostate cancer tumors. In this regard, we suggest that miR-182-5p may be a key androgen receptor-regulated factor that contributes to the development and metastasis of Chinese prostate cancers and may be a potential target for the early diagnosis and therapeutic studies of prostate cancer. -- Highlights: •miR-182-5p is the mostly up-regulated miRNA in Chinese prostate cancer. •miR-182-5p is regulated by androgen receptor. •miR-182-5p promotes prostate cancer progression. •miR-182-5p regulates ARRDC3/ITGB4 pathway.

  18. Efficacy of walking exercise in promoting cognitive-psychosocial functions in men with prostate cancer receiving androgen deprivation therapy

    Directory of Open Access Journals (Sweden)

    Lee C

    2012-07-01

    Full Text Available Abstract Background Prostate cancer is the most commonly diagnosed non-melanoma cancer among men. Androgen deprivation therapy (ADT has been the core therapy for men with advanced prostate cancer. It is only in recent years that clinicians began to recognize the cognitive-psychosocial side effects from ADT, which significantly compromise the quality of life of prostate cancer survivors. The objectives of the study are to determine the efficacy of a simple and accessible home-based, walking exercise program in promoting cognitive and psychosocial functions of men with prostate cancer receiving ADT. Methods A 6-month prospective, single-blinded, randomized controlled trial will be conducted to compare the Exercise Group with the Control Group. Twenty men with prostate cancer starting ADT will be recruited and randomly assigned to one of the two groups: the Exercise Group will receive instructions in setting up an individualized 6-month home-based, walking exercise program, while the Control Group will receive standard medical advice from the attending physician. The primary outcomes will be psychosocial and cognitive functions. Cognitive functions including memory, attention, working memory, and executive function will be assessed using a battery of neurocognitive tests at baseline and 6 months. Psychosocial functions including depression, anxiety and self-esteem will be assessed at baseline, 3 and 6 months using the Center for Epidemiological Studies Depression Scale, Spielberger State-Trait Anxiety Inventory, and Rosenberg Self-Esteem Scale. Discussion The significance of the cognitive-psychosocial side effects of ADT in men with prostate cancer has only been recently recognized, and the management remains unclear. This study addresses this issue by designing a simple and accessible home-based, exercise program that may potentially have significant impact on reducing the cognitive and psychosocial side effects of ADT, and ultimately

  19. Can androgen-deprivation therapy obviate the need of channel transurethral resection of the prostate in advanced prostate cancer with urinary retention? A prospective study

    Directory of Open Access Journals (Sweden)

    Rajeev Sood

    2017-12-01

    Full Text Available Objective: To evaluate the efficacy of androgen-deprivation therapy (ADT in relieving urinary retention in patients with advanced prostate cancer presenting with urinary retention or a high post-void residual urine volume (PVR. Patients and methods: Patients with advanced prostate cancer with an indwelling catheter for acute/chronic urinary retention, or with a high PVR (>200 mL who had not received any previous treatment were included in the study. Patients with localised prostate cancer eligible for receiving any therapy aimed at cure were excluded. All enrolled patients were managed by ADT (LHRH antagonist/agonist or orchidectomy combined with α-adrenoceptor antagonist/combined therapy for at least 1 month to a maximum of 3 months; they were given their first trial of voiding without catheter after 1 month, and monthly thereafter. Results: A total of 101 patients received ADT of which 97 were able to void successfully at the end of 3 months. In all, 27 patients could void in the first month, followed by 50 in the second month, and an additional 20 in the third month. There was a significant decrease in prostate volume, PVR, and International Prostate Symptom Score, and maximum urinary flow rates improved with normalisation of renal functions and resolution of upper tract changes noted on ultrasonography. Conclusion: ADT can relieve retention and decrease PVR over a period of time obviating the need for channel transurethral resection of the prostate. Keywords: ADT, ADT in retention, Prostate cancer

  20. The perspective of prostate cancer patients and patients' partners on the psychological burden of androgen deprivation and the dyadic adjustment of prostate cancer couples.

    Science.gov (United States)

    Hamilton, Lisa Dawn; Van Dam, Dexter; Wassersug, Richard J

    2016-07-01

    Prostate cancer and its treatments, particularly androgen deprivation therapy (ADT), affect both patients and partners. This study assessed how prostate cancer treatment type, patient mood, and sexual function related to dyadic adjustment from patient and partner perspectives. Men with prostate cancer (n = 206) and partners of men with prostate cancer (n = 66) completed an online survey assessing the patients' mood (profile of mood states short form), their dyadic adjustment (dyadic adjustment scale), and sexual function (expanded prostate cancer index composite). Analyses of covariance found that men on ADT reported better dyadic adjustment compared with men not on ADT. Erectile dysfunction was high for all patients, but a multivariate analysis of variance found that those on ADT experienced greater bother at loss of sexual function than patients not on ADT, suggesting that loss of libido when on ADT does not mitigate the psychological distress associated with loss of erections. In a multiple linear regression, patients' mood predicted their dyadic adjustment, such that worse mood was related to worse dyadic adjustment. However, more bother with patients' overall sexual function predicted lower relationship scores for the patients, while the patients' lack of sexual desire predicted lower dyadic adjustment for partners. Both patients and partners are impacted by the prostate cancer treatment effects on patients' psychological and sexual function. Our data help clarify the way that prostate cancer treatments can affect relationships and that loss of libido on ADT does not attenuate distress about erectile dysfunction. Understanding these changes may help patients and partners maintain a co-supportive relationship. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

  1. Impact of Androgen Deprivation Therapy on Self-reported Cognitive Function in Men with Prostate Cancer.

    Science.gov (United States)

    Marzouk, Shireen; Naglie, Gary; Tomlinson, George; Duff Canning, Sarah; Breunis, Henriette; Timilshina, Narhari; Alibhai, Shabbir M H

    2018-02-22

    Although androgen deprivation therapy (ADT) is widely used to treat prostate cancer (PC), its effects on cognitive function are unclear, and no prior report has examined the impact of ADT on self-reported cognitive function. Three groups of men age 50 or older and matched on age and education were enrolled: PC patients starting continuous ADT (n=81), PC patients not receiving ADT (PC controls, n=84), and healthy controls (n=85). Two scales from the Functional Assessment of Cancer Therapy-Cognitive Questionnaire (FACT-Cog) version 3 were used to assess self-reported cognitive function. Changes in cognitive scores over time were analyzed using two approaches: multivariable regression and calculation of the proportion of subjects per group with declines of 1-SD or more. Multivariable regression was used to assess predictors of decline in self-reported cognitive function. Relationships between the FACT-Cog and a neuropsychological battery of 15 tests were also examined. The mean age of participants was 69 years (range 50-87) and their mean educational level was 15 years (range 8-24). FACT-Cog scores were similar at baseline across cohorts. Neither analytic approach found ADT use to be associated with changes in self-reported cognitive function on either FACT-Cog scale. Mood and fatigue were correlated with changes in self-reported cognitive function. The relationship between self-reported and objective cognitive measures was weak (maximum Spearman correlation coefficient of 0.14) and only two of 30 correlations were statistically significant. Twelve months of ADT was not associated with self-reported cognitive function in older men with non-metastatic PC. Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  2. Persistence of senescent prostate cancer cells following prolonged neoadjuvant androgen deprivation therapy.

    Directory of Open Access Journals (Sweden)

    Michael L Blute

    Full Text Available Androgen deprivation therapy (ADT commonly leads to incomplete cell death and the fate of persistent cells involves, in part, a senescent phenotype. Senescence is terminal growth arrest in response to cell stress that is characterized by increased lysosomal-β-galactosidase (GLB1 the origin of senescence associated-β-gal activity (SA-β-gal. In the current study senescence is examined in vivo after ADT use in a neoadjuvant trial.Tissue microarrays were generated from prostate cancer specimens (n = 126 from a multicenter neoadjuvant ADT trial. Arrays were subjected to multiplexed immunofluorescent staining for GLB1, Ki67, cleaved caspase 3 (CC3 and E-cadherin. Automated quantitative imaging was performed using Vectra™ and expression correlated with clinicopathologic features.Tissue was analyzed from 59 patients treated with neoadjuvant ADT and 67 receiving no therapy preoperatively. Median follow-up was 85.3 mo and median ADT treatment was 5 mo. In PC treated with neoadjuvant ADT, GLB1 expression increased in intermediate Gleason score (GS 6-7; p = 0.001, but not high grade (GS 8-10 cancer. Significantly higher levels of GLB1 were seen in tissues undergoing neoadjuvant ADT longer than 5 months compared to untreated tissues (p = 0.002. In contrast, apoptosis significantly increased earlier (1-4 mo after ADT treatment (p<0.5.Increased GLB1 after neoadjuvant ADT occurs primarily among more clinically favorable intermediate grade cancers and enrichment of the phenotype occurs in a temporally prolonged fashion. Senescence may explain the persistence of PCa cells after ADT. Given concerns for the detrimental longer term presence of senescent cells, targeting these cells for removal may improve outcomes.

  3. Maximal exercise testing of men with prostate cancer being treated with androgen deprivation therapy.

    Science.gov (United States)

    Wall, Bradley A; Galvão, Daniel A; Fatehee, Naeem; Taaffe, Dennis R; Spry, Nigel; Joseph, David; Newton, Robert U

    2014-12-01

    Exercise is being increasingly established as a key adjuvant therapy in clinical oncology. As research has demonstrated the beneficial effect of exercise for cancer management, a growing number of patients with cancer are undertaking structured exercise programs. This study aimed to determine the safety and feasibility of formal exercise testing in clinical settings as it is becoming increasingly used as a screening tool and for exercise prescription purposes. One hundred and twelve patients with prostate cancer undergoing androgen deprivation therapy (ADT) took part in a physician-supervised multistage maximal stress test (Bruce protocol). Sixty patients had been on ADT for 3 months (chronic). Of these men, 85% were able to meet the criteria for the attainment of V˙O2max, whereas three positive tests (3.2%) were observed. The three participants who recorded a positive stress test underwent further medical examination and were subsequently cleared of clinically significant cardiovascular disease. Apart from the relatively low V˙O2max (24.7 ± 6.0 mL·kg·min, 10th-15th percentile), compared with normative data in healthy age-matched controls, the cardiovascular response to exercise was similar in this cancer population. Moreover, treatment duration did not seem to influence cardiovascular responses to exercise. This early evidence suggests that risk of adverse events during maximal exercise testing is relatively low in this population and certainly no higher than that in ages-matched, apparently healthy individuals. Maximal exercise testing was demonstrated to be feasible and safe, providing a direct assessment of V˙O2max. The relatively low number of positive tests in this study suggests that the risk of adverse events is relatively low in this population and certainly no higher than that in age-matched, apparently healthy individuals.

  4. Small Molecule Antagonists of the Nuclear Androgen Receptor for the Treatment of Castration-Resistant Prostate Cancer.

    Science.gov (United States)

    Johnson, James K; Skoda, Erin M; Zhou, Jianhua; Parrinello, Erica; Wang, Dan; O'Malley, Katherine; Eyer, Benjamin R; Kazancioglu, Mustafa; Eisermann, Kurtis; Johnston, Paul A; Nelson, Joel B; Wang, Zhou; Wipf, Peter

    2016-08-11

    After a high-throughput screening campaign identified thioether 1 as an antagonist of the nuclear androgen receptor, a zone model was developed for structure-activity relationship (SAR) purposes and analogues were synthesized and evaluated in a cell-based luciferase assay. A novel thioether isostere, cyclopropane (1S,2R)-27, showed the desired increased potency and structural properties (stereospecific SAR response, absence of a readily oxidized sulfur atom, low molecular weight, reduced number of flexible bonds and polar surface area, and drug-likeness score) in the prostate-specific antigen luciferase assay in C4-2-PSA-rl cells to qualify as a new lead structure for prostate cancer drug development.

  5. Prostate-Specific Antigen (PSA) Bounce After Dose-Escalated External Beam Radiation Therapy Is an Independent Predictor of PSA Recurrence, Metastasis, and Survival in Prostate Adenocarcinoma Patients.

    Science.gov (United States)

    Romesser, Paul B; Pei, Xin; Shi, Weiji; Zhang, Zhigang; Kollmeier, Marisa; McBride, Sean M; Zelefsky, Michael J

    2018-01-01

    To evaluate the difference in prostate-specific antigen (PSA) recurrence-free, distant metastasis-free, overall, and cancer-specific survival between PSA bounce (PSA-B) and non-bounce patients treated with dose-escalated external beam radiation therapy (DE-EBRT). During 1990-2010, 1898 prostate adenocarcinoma patients were treated with DE-EBRT to ≥75 Gy with ≥5 years follow-up. Patients receiving neoadjuvant/concurrent androgen-deprivation therapy (n=1035) or with fewer than 4 PSA values obtained 6 months or more after post-EBRT completion (n=87) were excluded. The evaluable 776 patients were treated (median, 81.0 Gy). Prostate-specific antigen bounce was defined as a ≥0.2-ng/mL increase above the interval PSA nadir, followed by a decrease to nadir or below. Prostate-specific antigen relapse was defined as post-radiation therapy PSA nadir + 2 ng/mL. Median follow-up was 9.2 years (interquartile range, 6.9-11.3 years). One hundred twenty-three patients (15.9%) experienced PSA-B after DE-EBRT at a median of 24.6 months (interquartile range, 16.1-38.5 months). On multivariate analysis, younger age (P=.001), lower Gleason score (P=.0003), and higher radiation therapy dose (P=.0002) independently predicted PSA-B. Prostate-specific antigen bounce was independently associated with decreased risk for PSA relapse (hazard ratio [HR] 0.53; 95% confidence interval [CI] 0.33-0.85; P=.008), distant metastatic disease (HR 0.34; 95% CI 0.12-0.94; P=.04), and all-cause mortality (HR 0.53; 95% CI 0.29-0.96; P=.04) on multivariate Cox analysis. Because all 50 prostate cancer-specific deaths in patients without PSA-B were in the non-bounce cohort, competing-risks analysis was not applicable. A nonparametric competing-risks test demonstrated that patients with PSA-B had superior cancer-specific survival compared with patients without PSA-B (P=.004). Patients treated with dose-escalated radiation therapy for prostate adenocarcinoma who experience posttreatment PSA-B have

  6. Down-regulation of DcR2 sensitizes androgen-dependent prostate cancer LNCaP cells to TRAIL-induced apoptosis

    Directory of Open Access Journals (Sweden)

    Vindrieux David

    2011-12-01

    Full Text Available Abstract Background Dysregulation of many apoptotic related genes and androgens are critical in the development, progression, and treatment of prostate cancer. The differential sensitivity of tumour cells to TRAIL-induced apoptosis can be mediated by the modulation of surface TRAIL receptor expression related to androgen concentration. Our previous results led to the hypothesis that downregulation of TRAIL-decoy receptor DcR2 expression following androgen deprivation would leave hormone sensitive normal prostate cells vulnerable to the cell death signal generated by TRAIL via its pro-apoptotic receptors. We tested this hypothesis under pathological conditions by exploring the regulation of TRAIL-induced apoptosis related to their death and decoy receptor expression, as also to hormonal concentrations in androgen-sensitive human prostate cancer, LNCaP, cells. Results In contrast to androgen-insensitive PC3 cells, decoy (DcR2 and death (DR5 receptor protein expression was correlated with hormone concentrations and TRAIL-induced apoptosis in LNCaP cells. Silencing of androgen-sensitive DcR2 protein expression by siRNA led to a significant increase in TRAIL-mediated apoptosis related to androgen concentration in LNCaP cells. Conclusions The data support the hypothesis that hormone modulation of DcR2 expression regulates TRAIL-induced apoptosis in LNCaP cells, giving insight into cell death induction in apoptosis-resistant hormone-sensitive tumour cells from prostate cancer. TRAIL action and DcR2 expression modulation are potentially of clinical value in advanced tumour treatment.

  7. Antilipolytic drug boosts glucose metabolism in prostate cancer

    DEFF Research Database (Denmark)

    Andersen, Kim Francis; Divilov, Vadim; Koziorowski, Jacek

    2013-01-01

    The antilipolytic drug Acipimox reduces free fatty acid (FFA) levels in the blood stream. We examined the effect of reduced FFAs on glucose metabolism in androgen-dependent (CWR22Rv1) and androgen-independent (PC3) prostate cancer (PCa) xenografts.......The antilipolytic drug Acipimox reduces free fatty acid (FFA) levels in the blood stream. We examined the effect of reduced FFAs on glucose metabolism in androgen-dependent (CWR22Rv1) and androgen-independent (PC3) prostate cancer (PCa) xenografts....

  8. Enhancement of Intermittent Androgen Ablation Therapy by Finasteride Administration in Animal Models

    National Research Council Canada - National Science Library

    Wang, Zhou

    2003-01-01

    .... Intermittent androgen ablation therapy may slow down the development of androgen refractory tumors because intermittent recovery of androgens can induce differentiation of prostatic epithelial cells...

  9. Enhancement of Intermittent Androgen Ablation Therapy by Finasteride Administration in Animal Models

    National Research Council Canada - National Science Library

    Wang, Zhou

    2005-01-01

    .... Intermittent androgen ablation therapy may slow down the development of androgen refractory tumors because intermittent recovery of androgens can induce differentiation of prostatic epithelial cells...

  10. Enhancement of Intermittent Androgen Ablation Therapy by Finasteride Administration in Animal Models

    National Research Council Canada - National Science Library

    Wang, Zhou

    2006-01-01

    .... Intermittent androgen ablation therapy (IAAT) may slow down the development of androgen refractory tumors because intermittent recovery of androgens can induce differentiation of prostatic epithelial cells...

  11. Enhancement of Intermittent Androgen Ablation Therapy by Finasteride Administration in Animal Models

    National Research Council Canada - National Science Library

    Wang, Zhou

    2004-01-01

    .... Intermittent androgen ablation therapy may slow down the development of androgen refractory tumors because intermittent recovery of androgens can induce differentiation of prostatic epithelial cells...

  12. The androgen receptor plays different roles in macrophage-induced proliferation in prostate stromal cells between transitional and peripheral zones of benign prostatic hypertrophy.

    Science.gov (United States)

    Xu, Dongliang; Wang, Xingjie; Jiang, Chenyi; Ruan, Yuan; Xia, Shujie; Wang, Xiaohai

    2017-01-01

    Macrophages play a critical role in the process of excessive stromal proliferation of benign prostatic hyperplasia (BPH). In our previous study, we used a BPH mouse model to elucidate a potential mechanism whereby macrophage infiltration promotes stromal cell proliferation in the prostate via the androgen receptor (AR)/inflammatory cytokine CCL3-dependent pathway. In our present study, we used the co-culture system of human macrophages and various prostatic zone stromal cells to further demonstrate that infiltrating macrophages promote prostatic stromal cell proliferation through stromal AR-dependent pathways, and we show that the stroma of TZ and PZ respond to macrophages differently because of differences in stromal AR signaling; this could possibly be one of the key pathways for stromal expansion during BPH development and progression. We hypothesize that AR and different downstream inflammatory mediators between TZ and PZ could serve as potential targets for the future design of therapeutic agents for BPH and our results provide significant insights into the search for targeted therapeutic approaches to battle BPH.

  13. Contribution of allelic variability in prostate specific antigen (PSA) & androgen receptor (AR) genes to serum PSA levels in men with prostate cancer.

    Science.gov (United States)

    Chavan, Sushant V; Maitra, Anurupa; Roy, Nobhojit; Chavan, Padma R

    2014-03-01

    Wide variability in serum prostate specific antigen (PSA) levels exists in malignant conditions of the prostate. PSA is expressed in normal range in 20 to 25 per cent of prostate cancer cases even in presence of high grade Gleason score. This study was aimed to assess the influence of genetic variants exhibited by PSA and androgen receptor (AR) genes towards the variable expression of PSA in prostate cancer. Pre-treatment serum PSA levels from 101 prostate cancer cases were retrieved from medical record. PSA genotype analysis in promoter region and AR gene microsatellite Cytosine/Adenine/Guanine (CAG) repeat analysis in exon 1 region was performed using DNA sequencing and fragment analysis techniques. A total of seven single nucleotide polymorphisms (SNPs) in the PSA promoter region were noted. Only two SNPs viz., 158G/A (PPSA levels. The carriers of homozygous GG genotype (PPSA whereas homozygous AA genotype (PPSA levels. The combination effect of PSA genotypes along with stratified AR CAG repeats lengths (long, intermediate and short) was also studied. The homozygous GG genotype along with AR long CAG repeats and homozygous AA genotype along with AR short CAG repeats at position -3845 and -158 showed strong interaction and thus influenced serum PSA levels. The genetic variants exhibited by PSA gene at positions -3845G/A and -158G/A may be accountable towards wide variability of serum PSA levels in prostate cancer. Also the preferential binding of G and A alleles at these polymorphic sites along with AR long and short CAG repeats may contribute towards PSA expression.

  14. The Response of Prostate Smooth Muscle Cells to Testosterone Is Determined by the Subcellular Distribution of the Androgen Receptor.

    Science.gov (United States)

    Peinetti, Nahuel; Scalerandi, María Victoria; Cuello Rubio, Mariana Micaela; Leimgruber, Carolina; Nicola, Juan Pablo; Torres, Alicia Ines; Quintar, Amado Alfredo; Maldonado, Cristina Alicia

    2018-02-01

    Androgen signaling in prostate smooth muscle cells (pSMCs) is critical for the maintenance of prostate homeostasis, the alterations of which are a central aspect in the development of pathological conditions. Testosterone can act through the classic androgen receptor (AR) in the cytoplasm, eliciting genomic signaling, or through different types of receptors located at the plasma membrane for nongenomic signaling. We aimed to find evidence of nongenomic testosterone-signaling mechanisms in pSMCs and their participation in cell proliferation, differentiation, and the modulation of the response to lipopolysaccharide. We demonstrated that pSMCs can respond to testosterone by a rapid activation of ERK1/2 and Akt. Furthermore, a pool of ARs localized at the cell surface of pSMCs is responsible for a nongenomic testosterone-induced increase in cell proliferation. Through membrane receptor stimulation, testosterone favors a muscle phenotype, indicated by an increase in smooth muscle markers. We also showed that the anti-inflammatory effects of testosterone, capable of attenuating lipopolysaccharide-induced proinflammatory actions, are promoted only by receptors located inside the cell. We postulate that testosterone might perform prohomeostatic effects through intracellular-initiated mechanisms by modulating cell proliferation and inflammation, whereas some pathological, hyperproliferative actions would be induced by membrane-initiated nongenomic signaling in pSMCs. Copyright © 2018 Endocrine Society.

  15. Using Human Stem Cells to Study the Role of the Stroma in the Initiation of Prostate Cancer

    Science.gov (United States)

    2011-03-01

    process of benign prostatic hyperplasia. Prostate. Supplement 2 33–50. (doi:10.1002/pros.2990150506) Iwata T, Schultz D, Hicks J, Hubbard GK, Mutton...0905524107) Montpetit M, Abrahams P, Clark AF & Tenniswood M 1988 Androgen-independent epithelial cells of the rat ventral prostate. Prostate 12 13–28

  16. Measurements of free and total PSA, tissue polypeptide-specific antigen (TPS), and CYFRA 21-1 in prostate cancer patients under intermittent androgen suppression therapy.

    Science.gov (United States)

    Theyer, G; Dürer, A; Theyer, U; Haberl, I; Ulsperger, E; Baumgartner, G; Hamilton, G

    1999-10-01

    The present study evaluated monthly measurements of free and total prostate-specific antigen (PSA), and the tumor proliferation markers tissue polypeptide-specific antigen (TPS) and cytokeratin fragment 21-1 (CYFRA 21-1) in patients with advanced prostate cancer receiving intermittent androgen suppression therapy (IAS). Thirty-four men received alternating cycles of 8 month androgen suppression and treatment cessation (mean duration, 10.3 months) until PSA increased to >20 microg/l. Measurements of testosterone, percentage of free PSA, TPS, and CYFRA 21-1 were performed using ELISA and RIA assays. Periods of androgen suppression resulted in reversible reductions of testosterone (from 6 +/- 0.8 to IAS cycle. TPS showed a decrease of 50% after 3 months, and CYFRA 21-1 a 25% decrease after 7 months of androgen suppression treatment. During treatment cessation, TPS exceeded the normal cutoff value of 90 U/l late in tumor regrowth (9-11 months), whereas CYFRA 21-1 remained below the normal cutoff value of 3.3 ng/ml. PSA is the best and most sensitive marker of prostate cancer regression and regrowth during IAS cycles of the markers tested in this study. Free PSA constitutes approximately 15% of total PSA (range, 5-32%), and its percentage showed no significant change during IAS cycles. The TPS and CYFRA 21-1 proliferation marker changes in IAS seem to be related mainly to effects on normal androgen-dependent tissues. Copyright 1999 Wiley-Liss, Inc.

  17. Fenofibrate down-regulates the expressions of androgen receptor (AR) and AR target genes and induces oxidative stress in the prostate cancer cell line LNCaP

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Hu; Zhu, Chen; Qin, Chao [State Key Laboratory of Reproductive Medicine, Department of Urology, First Affiliated Hospital of Nanjing Medical University, Nanjing (China); Tao, Tao [Department of Neurosurgery, First Affiliated Hospital of Nanjing Medical University, Nanjing (China); Li, Jie; Cheng, Gong; Li, Pu; Cao, Qiang; Meng, Xiaoxin; Ju, Xiaobing; Shao, Pengfei; Hua, Lixin [State Key Laboratory of Reproductive Medicine, Department of Urology, First Affiliated Hospital of Nanjing Medical University, Nanjing (China); Gu, Min, E-mail: medzhao1980@163.com [State Key Laboratory of Reproductive Medicine, Department of Urology, First Affiliated Hospital of Nanjing Medical University, Nanjing (China); Yin, Changjun, E-mail: drcjyin@gmail.com [State Key Laboratory of Reproductive Medicine, Department of Urology, First Affiliated Hospital of Nanjing Medical University, Nanjing (China)

    2013-03-08

    Highlights: ► Fenofibrate induces cell cycle arrest in G1 phase and apoptosis in LNCaP cells. ► Fenofibrate reduces the expressions of androgen receptor in LNCaP cells. ► Fenofibrate induces oxidative stress in the prostate cancer cell line LNCaP. -- Abstract: Fenofibrate, a peroxisome proliferator-androgen receptor-alpha agonist, is widely used in treating different forms of hyperlipidemia and hypercholesterolemia. Recent reports have indicated that fenofibrate exerts anti-proliferative and pro-apoptotic properties. This study aims to investigate the effects of fenofibrate on the prostate cancer (PCa) cell line LNCaP. The effects of fenofibrate on LNCaP cells were evaluated by flow cytometry, reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assays, Western blot analysis, and dual-luciferase reporter assay. Fenofibrate induces cell cycle arrest in G1 phase and apoptosis in LNCaP cells, reduces the expressions of androgen receptor (AR) and AR target genes (prostate-specific antigen and TMPRSS2), and inhibits Akt phosphorylation. Fenofibrate can induce the accumulation of intracellular reactive oxygen species and malondialdehyde, and decrease the activities of total anti-oxidant and superoxide dismutase in LNCaP cells. Fenofibrate exerts an anti-proliferative property by inhibiting the expression of AR and induces apoptosis by causing oxidative stress. Therefore, our data suggest fenofibrate may have beneficial effects in fenofibrate users by preventing prostate cancer growth through inhibition of androgen activation and expression.

  18. Significance of pretreatment cardiovascular morbidity as a risk factor during treatment with parenteral oestrogen or combined androgen deprivation of 915 patients with metastasized prostate cancer

    DEFF Research Database (Denmark)

    Johansson, Robert; Damber, Jan Erik; Hagerman, Inger

    2011-01-01

    This study aimed to evaluate prognostic risk factors for cardiovascular events during treatment of metastatic prostate cancer patients with high-dose parenteral polyoestradiol phosphate (PEP, Estradurin®) or combined androgen deprivation (CAD) with special emphasis on pretreatment cardiovascular...... disease....

  19. Nrdp1-Mediated ErbB3 Increase during Androgen Ablation and its Contribution to Androgen-Independence

    Science.gov (United States)

    2013-04-01

    Gene Ontology Consortium. Nat Genet. 2000; 25(1):25–29. [PubMed: 10802651] 3. Bathgate RA, Samuel CS, Burazin TC, Gundlach AL, Tregear GW. Relaxin: new...prostate cancer. N Engl J Med. 2004; 351(15):1513–1520. [PubMed: 15470214] 31. Samuel CS, Tian H, Zhao L, Amento EP. Relaxin is a key mediator of...Pathology 146 1368–1375. deVere White RW, Hackman RM, Soares SE, Beckett LA, Li Y & Sun B 2004 Effects of a genistein-rich extract on PSA levels in men with a

  20. Cystatin C is downregulated in prostate cancer and modulates invasion of prostate cancer cells via MAPK/Erk and androgen receptor pathways.

    Science.gov (United States)

    Wegiel, Barbara; Jiborn, Thomas; Abrahamson, Magnus; Helczynski, Leszek; Otterbein, Leo; Persson, Jenny Liao; Bjartell, Anders

    2009-11-23

    Cystatin C is believed to prevent tumor progression by inhibiting the activities of a family of lysosomal cysteine proteases. However, little is known about the precise mechanism of cystatin C function in prostate cancer. In the present study, we examined the expression of cystatin C and its association with matrix metalloproteinases 2 (MMP2) and androgen receptor (AR) in a tissue microarray comparing benign and malignant specimens from 448 patients who underwent radical prostatectomy for localized prostate cancer. Cystatin C expression was significantly lower in cancer specimens than in benign tissues (pcystatin C and MMP2 (r(s) (2) = -0.056, p = 0.05). There was a clear trend that patients with decreased level of cystatin C had lower overall survival. Targeted inhibition of cystatin C using specific siRNA resulted in an increased invasiveness of PC3 cells, whereas induction of cystatin C overexpression greatly reduced invasion rate of PC3 in vitro. The effect of cystatin C on modulating the PC3 cell invasion was provoked by Erk2 inhibitor that specifically inhibited MAPK/Erk2 activity. This suggests that cystatin C may mediate tumor cell invasion by modulating the activity of MAPK/Erk cascades. Consistent with our immunohistochemical findings that patients with low expression of cystatin C and high expression of androgen receptor (AR) tend to have worse overall survival than patients with high expression of cystatin C and high AR expression, induced overexpression of AR in PC3 cells expressing cystatin C siRNA greatly enhanced the invasiveness of PC3 cells. This suggests that there may be a crosstalk between cystatin C and AR-mediated pathways. Our study uncovers a novel role for cystatin C and its associated cellular pathways in prostate cancer invasion and metastasis.

  1. Cystatin C is downregulated in prostate cancer and modulates invasion of prostate cancer cells via MAPK/Erk and androgen receptor pathways.

    Directory of Open Access Journals (Sweden)

    Barbara Wegiel

    Full Text Available Cystatin C is believed to prevent tumor progression by inhibiting the activities of a family of lysosomal cysteine proteases. However, little is known about the precise mechanism of cystatin C function in prostate cancer. In the present study, we examined the expression of cystatin C and its association with matrix metalloproteinases 2 (MMP2 and androgen receptor (AR in a tissue microarray comparing benign and malignant specimens from 448 patients who underwent radical prostatectomy for localized prostate cancer. Cystatin C expression was significantly lower in cancer specimens than in benign tissues (p<0.001 and there was a statistically significant inverse correlation between expression of cystatin C and MMP2 (r(s (2 = -0.056, p = 0.05. There was a clear trend that patients with decreased level of cystatin C had lower overall survival. Targeted inhibition of cystatin C using specific siRNA resulted in an increased invasiveness of PC3 cells, whereas induction of cystatin C overexpression greatly reduced invasion rate of PC3 in vitro. The effect of cystatin C on modulating the PC3 cell invasion was provoked by Erk2 inhibitor that specifically inhibited MAPK/Erk2 activity. This suggests that cystatin C may mediate tumor cell invasion by modulating the activity of MAPK/Erk cascades. Consistent with our immunohistochemical findings that patients with low expression of cystatin C and high expression of androgen receptor (AR tend to have worse overall survival than patients with high expression of cystatin C and high AR expression, induced overexpression of AR in PC3 cells expressing cystatin C siRNA greatly enhanced the invasiveness of PC3 cells. This suggests that there may be a crosstalk between cystatin C and AR-mediated pathways. Our study uncovers a novel role for cystatin C and its associated cellular pathways in prostate cancer invasion and metastasis.

  2. Inhibition of Androgen Receptor Function and Level in Castration-Resistant Prostate Cancer Cells by 2-[(isoxazol-4-ylmethyl)thio]-1-(4-phenylpiperazin-1-yl)ethanone.

    Science.gov (United States)

    Masoodi, Khalid Z; Eisermann, Kurtis; Yang, Zhenyu; Dar, Javid A; Pascal, Laura E; Nguyen, Minh; O'Malley, Katherine; Parrinello, Erica; Feturi, Firuz G; Kenefake, Alex N; Nelson, Joel B; Johnston, Paul A; Wipf, Peter; Wang, Zhou

    2017-10-01

    The androgen receptor (AR) plays a critical role in the development of castration-resistant prostate cancer (CRPC) as well as in the resistance to the second-generation AR antagonist enzalutamide and the selective inhibitor of cytochrome P450 17A1 (CYP17A1) abiraterone. Novel agents targeting AR may inhibit the growth of prostate cancer cells resistant to enzalutamide and/or abiraterone. Through a high-throughput/high-content screening of a 220,000-member small molecule library, we have previously identified 2-[(isoxazol-4-ylmethyl)thio]-1-(4-phenylpiperazin-1-yl)ethanone (IMTPPE) (SID 3712502) as a novel small molecule capable of inhibiting AR transcriptional activity and protein level in C4-2 prostate cancer cells. In this study, we show that IMTPPE inhibits AR-target gene expression using real-time polymerase chain reaction, Western blot, and luciferase assays. IMTPPE inhibited proliferation of AR-positive, but not AR-negative, prostate cancer cells in culture. IMTPPE inhibited the transcriptional activity of a mutant AR lacking the ligand-binding domain (LBD), indicating that IMTPPE inhibition of AR is independent of the LBD. Furthermore, animal studies showed that IMTPPE inhibited the growth of 22Rv1 xenograft tumor, a model for enzalutamide-resistant prostate cancer. These findings suggest that IMTPPE is a potential lead compound for developing clinical candidates for the treatment of CRPC, including those resistant to enzalutamide. Copyright © 2017 Endocrine Society.

  3. Duration of Androgen Deprivation in Locally Advanced Prostate Cancer: Long-Term Update of NRG Oncology RTOG 9202

    Energy Technology Data Exchange (ETDEWEB)

    Lawton, Colleen A.F., E-mail: clawton@mcw.edu [Medical College of Wisconsin, Milwaukee, Wisconsin (United States); Lin, Xiaolei [University of Chicago, Chicago, Illinois (United States); Hanks, Gerald E. [Fox Chase Cancer Center, Philadelphia, Pennsylvania (United States); Lepor, Herbert [New York University, New York, New York (United States); Grignon, David J. [Indiana University, Indianapolis, Indiana (United States); Brereton, Harmar D. [Northeast Radiation Oncology Center, Dunmore, Pennsylvania (United States); Bedi, Meena [Medical College of Wisconsin, Milwaukee, Wisconsin (United States); Rosenthal, Seth A. [Sutter General Hospital, Sacramento, California (United States); Zeitzer, Kenneth L. [Albert Einstein Medical Center, Philadelphia, Pennsylvania (United States); Venkatesan, Varagur M. [London Regional Cancer Program, London, Ontario (Canada); Horwitz, Eric M. [Fox Chase Cancer Center, Philadelphia, Pennsylvania (United States); Pisansky, Thomas M. [Mayo Clinic, Rochester, Minnesota (United States); Kim, Harold [Wayne State University-Karmanos Cancer Institute, Detroit, Michigan (United States); Parliament, Matthew B. [Cross Cancer Institute, Edmonton, Alberta (Canada); Rabinovitch, Rachel [University of Colorado Denver, Denver, Colorado (United States); Roach, Mack [University of California, San Francisco, California (United States); Kwok, Young [University of Maryland Medical System, Baltimore, Maryland (United States); Dignam, James J. [University of Chicago, Chicago, Illinois (United States); NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania (United States); Sandler, Howard M. [Cedars-Sinai Medical Center, Los Angeles, California (United States)

    2017-06-01

    Purpose: Trial RTOG 9202 was a phase 3 randomized trial designed to determine the optimal duration of androgen deprivation therapy (ADT) when combined with definitive radiation therapy (RT) in the treatment of locally advanced nonmetastatic adenocarcinoma of the prostate. Long-term follow-up results of this study now available are relevant to the management of this disease. Methods and Materials: Men (N=1554) with adenocarcinoma of the prostate (cT2c-T4, N0-Nx) with a prostate-specific antigen (PSA) <150 ng/mL and no evidence of distant metastasis were randomized (June 1992 to April 1995) to short-term ADT (STAD: 4 months of flutamide 250 mg 3 times per day and goserelin 3.6 mg per month) and definitive RT versus long-term ADT (LTAD: STAD with definitive RT plus an additional 24 months of monthly goserelin). Results: Among 1520 protocol-eligible and evaluable patients, the median follow-up time for this analysis was 19.6 years. In analysis adjusted for prognostic covariates, LTAD improved disease-free survival (29% relative reduction in failure rate, P<.0001), local progression (46% relative reduction, P=.02), distant metastases (36% relative reduction, P<.0001), disease-specific survival (30% relative reduction, P=.003), and overall survival (12% relative reduction, P=.03). Other-cause mortality (non–prostate cancer) did not differ (5% relative reduction, P=.48). Conclusions: LTAD and RT is superior to STAD and RT for the treatment of locally advanced nonmetastatic adenocarcinoma of the prostate and should be considered the standard of care.

  4. Duration of Androgen Deprivation in Locally Advanced Prostate Cancer: Long-Term Update of NRG Oncology RTOG 9202

    International Nuclear Information System (INIS)

    Lawton, Colleen A.F.; Lin, Xiaolei; Hanks, Gerald E.; Lepor, Herbert; Grignon, David J.; Brereton, Harmar D.; Bedi, Meena; Rosenthal, Seth A.; Zeitzer, Kenneth L.; Venkatesan, Varagur M.; Horwitz, Eric M.; Pisansky, Thomas M.; Kim, Harold; Parliament, Matthew B.; Rabinovitch, Rachel; Roach, Mack; Kwok, Young; Dignam, James J.; Sandler, Howard M.

    2017-01-01

    Purpose: Trial RTOG 9202 was a phase 3 randomized trial designed to determine the optimal duration of androgen deprivation therapy (ADT) when combined with definitive radiation therapy (RT) in the treatment of locally advanced nonmetastatic adenocarcinoma of the prostate. Long-term follow-up results of this study now available are relevant to the management of this disease. Methods and Materials: Men (N=1554) with adenocarcinoma of the prostate (cT2c-T4, N0-Nx) with a prostate-specific antigen (PSA) <150 ng/mL and no evidence of distant metastasis were randomized (June 1992 to April 1995) to short-term ADT (STAD: 4 months of flutamide 250 mg 3 times per day and goserelin 3.6 mg per month) and definitive RT versus long-term ADT (LTAD: STAD with definitive RT plus an additional 24 months of monthly goserelin). Results: Among 1520 protocol-eligible and evaluable patients, the median follow-up time for this analysis was 19.6 years. In analysis adjusted for prognostic covariates, LTAD improved disease-free survival (29% relative reduction in failure rate, P<.0001), local progression (46% relative reduction, P=.02), distant metastases (36% relative reduction, P<.0001), disease-specific survival (30% relative reduction, P=.003), and overall survival (12% relative reduction, P=.03). Other-cause mortality (non–prostate cancer) did not differ (5% relative reduction, P=.48). Conclusions: LTAD and RT is superior to STAD and RT for the treatment of locally advanced nonmetastatic adenocarcinoma of the prostate and should be considered the standard of care.

  5. miR-1207-3p regulates the androgen receptor in prostate cancer via FNDC1/fibronectin

    International Nuclear Information System (INIS)

    Das, Dibash K.; Naidoo, Michelle; Ilboudo, Adeodat; Park, Jong Y.; Ali, Thahmina; Krampis, Konstantinos; Robinson, Brian D.; Osborne, Joseph R.; Ogunwobi, Olorunseun O.

    2016-01-01

    Prostate cancer (PCa) is frequently diagnosed in men, and dysregulation of microRNAs is characteristic of many cancers. MicroRNA-1207-3p is encoded at the non-protein coding gene locus PVT1 on the 8q24 human chromosomal region, an established PCa susceptibility locus. However, the role of microRNA-1207-3p in PCa is unclear. We discovered that microRNA-1207-3p is significantly underexpressed in PCa cell lines in comparison to normal prostate epithelial cells. Increased expression of microRNA-1207-3p in PCa cells significantly inhibits proliferation, migration, and induces apoptosis via direct molecular targeting of FNDC1, a protein which contains a conserved protein domain of fibronectin (FN1). FNDC1, FN1, and the androgen receptor (AR) are significantly overexpressed in PCa cell lines and human PCa, and positively correlate with aggressive PCa. Prostate tumor FN1 expression in patients that experienced PCa-specific death is significantly higher than in patients that remained alive. Furthermore, FNDC1, FN1 and AR are concomitantly overexpressed in metastatic PCa. Consequently, these studies have revealed a novel microRNA-1207-3p/FNDC1/FN1/AR regulatory pathway in PCa. - Graphical abstract: miR-1207-3p/FNDC1/FN1/AR is a novel regulatory pathway in prostate cancer. - Highlights: • Expression of microRNA-1207-3p is significantly lost in prostate cancer (PCa) cells. • MicroRNA-1207-3p regulates proliferation, apoptosis, and migration via direct molecular targeting of the 3′UTR of FNDC1. • MicroRNA-1207-3p regulates proliferation, apoptosis, and migration via direct molecular targeting of the 3′UTR of FNDC1. • FNDC1, FN1, and AR are concurrently overexpressed in metastatic PCa.

  6. miR-1207-3p regulates the androgen receptor in prostate cancer via FNDC1/fibronectin

    Energy Technology Data Exchange (ETDEWEB)

    Das, Dibash K. [Department of Biological Sciences, Hunter College of The City University of New York, New York, NY 10065 (United States); The Graduate Center Departments of Biology and Biochemistry, The City University of New York, New York, NY 10016 (United States); Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY 10065 (United States); Naidoo, Michelle; Ilboudo, Adeodat [Department of Biological Sciences, Hunter College of The City University of New York, New York, NY 10065 (United States); Park, Jong Y. [Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida 33612 (United States); Ali, Thahmina [Department of Biological Sciences, Hunter College of The City University of New York, New York, NY 10065 (United States); Krampis, Konstantinos [Department of Biological Sciences, Hunter College of The City University of New York, New York, NY 10065 (United States); Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Cornell Medicine, Cornell University, New York, NY 10065 (United States); Robinson, Brian D. [Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, Cornell University, New York, NY 10065 (United States); Department of Urology, Weill Cornell Medicine, Cornell University, New York, NY 10065 (United States); Osborne, Joseph R. [Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065 (United States); Ogunwobi, Olorunseun O., E-mail: ogunwobi@genectr.hunter.cuny.edu [Department of Biological Sciences, Hunter College of The City University of New York, New York, NY 10065 (United States); The Graduate Center Departments of Biology and Biochemistry, The City University of New York, New York, NY 10016 (United States); Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY 10065 (United States)

    2016-11-01

    Prostate cancer (PCa) is frequently diagnosed in men, and dysregulation of microRNAs is characteristic of many cancers. MicroRNA-1207-3p is encoded at the non-protein coding gene locus PVT1 on the 8q24 human chromosomal region, an established PCa susceptibility locus. However, the role of microRNA-1207-3p in PCa is unclear. We discovered that microRNA-1207-3p is significantly underexpressed in PCa cell lines in comparison to normal prostate epithelial cells. Increased expression of microRNA-1207-3p in PCa cells significantly inhibits proliferation, migration, and induces apoptosis via direct molecular targeting of FNDC1, a protein which contains a conserved protein domain of fibronectin (FN1). FNDC1, FN1, and the androgen receptor (AR) are significantly overexpressed in PCa cell lines and human PCa, and positively correlate with aggressive PCa. Prostate tumor FN1 expression in patients that experienced PCa-specific death is significantly higher than in patients that remained alive. Furthermore, FNDC1, FN1 and AR are concomitantly overexpressed in metastatic PCa. Consequently, these studies have revealed a novel microRNA-1207-3p/FNDC1/FN1/AR regulatory pathway in PCa. - Graphical abstract: miR-1207-3p/FNDC1/FN1/AR is a novel regulatory pathway in prostate cancer. - Highlights: • Expression of microRNA-1207-3p is significantly lost in prostate cancer (PCa) cells. • MicroRNA-1207-3p regulates proliferation, apoptosis, and migration via direct molecular targeting of the 3′UTR of FNDC1. • MicroRNA-1207-3p regulates proliferation, apoptosis, and migration via direct molecular targeting of the 3′UTR of FNDC1. • FNDC1, FN1, and AR are concurrently overexpressed in metastatic PCa.

  7. Prevalent and incident use of androgen deprivation therapy among men with prostate cancer in the United States.

    Science.gov (United States)

    Gilbert, Scott M; Kuo, Yong-Fang; Shahinian, Vahakn B

    2011-01-01

    Androgen deprivation therapy (ADT) for prostate cancer increased substantially through the 1990s, but more recent national trends regarding incident and prevalent use have been incompletely characterized. Linked Surveillance, Epidemiology, and End Results (SEER)-Medicare data were used to study patterns of ADT utilization. Prevalence of ADT in the male Medicare population was estimated by examining a cohort of prostate cancer patients and a 5% noncancer control population, from 1991 to 2005. ADT use across different indications was examined for men with incident cancers from 2000 to 2002. Nested logit models were used to examine determinants of ADT use in men with lower risk prostate cancer not treated definitively by surgery or radiation. Prevalent ADT use increased through the 1990s, peaked in 2000 at 3.17% of all male Medicare beneficiaries, subsequently stabilized, then dropped in 2005 to 2.92%. Between 2000 and 2002, use in incident prostate cancer was stable, with 44.8% use in all cases, 15% of cases as an adjuvant with radiation, and 14% as a primary therapy. In the nested logit model, predictors of ADT use in a lower risk setting were older age, higher stage and grade, and elevated prostate-specific antigen levels. Following a period of rapid expansion during the 1990s, incident and prevalent use of ADT has leveled, and may be starting to decline. Further research is needed to monitor how reductions in reimbursement for GnRH agonists will affect appropriate use of ADT as well as use in settings where its benefits may be marginal. Copyright © 2011 Elsevier Inc. All rights reserved.

  8. Identifying significant genetic regulatory networks in the prostate cancer from microarray data based on transcription factor analysis and conditional independency

    Directory of Open Access Journals (Sweden)

    Yeh Cheng-Yu

    2009-12-01

    Full Text Available Abstract Background Prostate cancer is a world wide leading cancer and it is characterized by its aggressive metastasis. According to the clinical heterogeneity, prostate cancer displays different stages and grades related to the aggressive metastasis disease. Although numerous studies used microarray analysis and traditional clustering method to identify the individual genes during the disease processes, the important gene regulations remain unclear. We present a computational method for inferring genetic regulatory networks from micorarray data automatically with transcription factor analysis and conditional independence testing to explore the potential significant gene regulatory networks that are correlated with cancer, tumor grade and stage in the prostate cancer. Results To deal with missing values in microarray data, we used a K-nearest-neighbors (KNN algorithm to determine the precise expression values. We applied web services technology to wrap the bioinformatics toolkits and databases to automatically extract the promoter regions of DNA sequences and predicted the transcription factors that regulate the gene expressions. We adopt the microarray datasets consists of 62 primary tumors, 41 normal prostate tissues from Stanford Microarray Database (SMD as a target dataset to evaluate our method. The predicted results showed that the possible biomarker genes related to cancer and denoted the androgen functions and processes may be in the development of the prostate cancer and promote the cell death in cell cycle. Our predicted results showed that sub-networks of genes SREBF1, STAT6 and PBX1 are strongly related to a high extent while ETS transcription factors ELK1, JUN and EGR2 are related to a low extent. Gene SLC22A3 may explain clinically the differentiation associated with the high grade cancer compared with low grade cancer. Enhancer of Zeste Homolg 2 (EZH2 regulated by RUNX1 and STAT3 is correlated to the pathological stage

  9. Prostate Cancer Metastases to Bone: Role of High Bone Turnover Induced by Androgen Deprivation

    National Research Council Canada - National Science Library

    Padalecki, Susan

    2002-01-01

    .... Treatment with androgen deprivation therapy leads to an increase in bone turnover as indicated by the loss of bone mineral density and the increase in markers of bone turnover in patients on treatment...

  10. Dutasteride and enzalutamide synergistically suppress prostate tumor cell proliferation

    NARCIS (Netherlands)

    Hamid, A.R.; Verhaegh, G.W.C.T.; Smit, F.P.; RIjt-van de Westerlo, C.; Armandari, I.; Brandt, A.; Sweep, F.C.; Sedelaar, J.P.M.; Schalken, J.A.

    2015-01-01

    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

  11. Long-term side-effects of intermittent androgen suppression therapy in prostate cancer: results of a phase II study.

    Science.gov (United States)

    Malone, Shawn; Perry, Gad; Segal, Roanne; Dahrouge, Simone; Crook, Juanita

    2005-09-01

    To assess the feasibility and tolerability of intermittent androgen suppression therapy (IAS) in prostate cancer. Patients with recurrent or metastic prostate cancer received cyclical periods of treatment with leuprolide acetate and nilutamide for 8 months, and rest periods. Cycles were repeated at progression until the treatment failed to achieve normal prostate-specific antigen (PSA) levels. Patients were followed with PSA level, testosterone level, haemoglobin level, weight and bone mineral density evaluations. The median time to treatment failure, recovery from anaemia, or normalization of testosterone level was estimated by the Kaplan-Meier method. In all, 95 patients received 245 cycles; the median duration of rest periods was 8 months and median time to treatment failure 47 months. Testosterone recovery during rest periods was documented in 117 (61%) of cycles. Anaemia was mild and reported in 33%, 44% and 67% of cycles 1, 2 and 3, respectively. Sexual function recovered during the rest periods in 47% of cycles. There was no significant overall change in body mass index at the end of the treatment period. Osteoporosis was documented in at least one site evaluated in 41 patients (37%). IAS has the potential to reduce side-effects, including recovery of haemoglobin level, return of sexual function and absence of weight gain at the end of the study period.

  12. Predictors of Fracture Risk and Bone Mineral Density in Men with Prostate Cancer on Androgen Deprivation Therapy

    Directory of Open Access Journals (Sweden)

    Katherine Neubecker

    2011-01-01

    Full Text Available Decrease of bone mineral density (BMD and fracture risk is increased in men with prostate cancer receiving androgen deprivation therapy (ADT. We looked at possible predictors of decreased BMD and increased fracture risk in men with prostate cancer; most of whom were on ADT. In a retrospective study, we analyzed serum, BMD, and clinical risk factors used in the Fracture Risk Assessment (FRAX tool and others in 78 men with prostate cancer with reported height loss. The subjects were divided in two groups: 22 men with and 56 without vertebral fractures. 17 of the 22 men with vertebral fractures on spine X-rays did not know they had a vertebral fracture. Of those 17 men, 9 had not previously qualified for treatment based on preradiograph FRAX score calculated with BMD, and 6 based on FRAX calculated without BMD. Performing spine films increased the predictive ability of FRAX for vertebral fracture. Vertebral fracture was better predicted by FRAX for other osteoporotic fractures than FRAX for hip fractures. The inclusion of BMD in FRAX calculations did not affect the predictive ability of FRAX. The PSA level showed a positive correlation with lumbar spine BMD and accounted for about 9% of spine BMD.

  13. Triptolide reduces prostate size and androgen level on testosterone-induced benign prostatic hyperplasia in Sprague Dawley rats.

    Science.gov (United States)

    Wang, Yu-Rong; Xu, Yuan; Jiang, Zhen-Zhou; Zhang, Lu-Yong; Wang, Tao

    2017-05-01

    Benign prostatic hyperplasia (BPH) is an age-related disease of unknown etiology, characterized by prostatic enlargement coincident with distinct alterations in tissue histology. In the present study, we investigated whether triptolide can prevent testosterone-induced prostatic hyperplasia in rats. Castration was performed via the scrotal route after urethane aesthesia. BPH was induced in experimental groups by daily subcutaneous injections of testosterone propionate (TP) for two weeks. Triptolide was administered daily by oral gavage at a dose of 100 and 50 μg·kg -1 for 2 weeks, along with the TP injections. On day 14, the animals were humanely killed by cervical dislocation after aesthesia. Prostates were excised, weighed, and used for histological studies. Testosterone and dihydrotestosterone (DHT) levels in serum and prostate were measured. The results showed that triptolide significantly reduced the prostate weight, and the testosterone and DHT levels in both the serum and prostate. Histopathological examination also showed that triptolide treatment suppressed TP-induced prostatic hyperplasia. In conclusion, triptolide effectively inhibits the development of BPH induced by testosterone in a rat model. Copyright © 2017 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

  14. Correction of androgen deficiency in chronic infectious prostatitis as pathogenetic method of overcoming inefficiencies standard antibiotics against the growing antibiotic resistance

    Directory of Open Access Journals (Sweden)

    I. A. Tyuzikov

    2014-11-01

    Full Text Available The chronic prostatitis occupies the big relative density in structure of an out-patient urological pathology in our country, however, results of its standard pharmacotherapy remain unsatisfactory that is accompanied by high risk clinical recurrence and progressing of anatomic and functional disorders in prostata. Modern methods of diagnostics of the chronic infectious prostatitis, which share in the general structure of inflammatory prostata diseases does not exceed 10 %, are based on the recommended volume of the standard tests directed only on revealing of the infectious agent in a prostatic secret, and do not consider degree of disorders of the prostatic homeostasis which key moment is prostata androgen-dependence. It leads to mainly symptomatic approach in treatment of a chronic infectious prostatitis in the modern urological practice, based exclusively on antibacterial therapy that promotes the further growth of prostate pathogens antibiotics resistance, inefficiencies of unreasonable repeated courses of antibacterial therapy and are supported by a myth about incurability of a chronic prostatitis. At the same time, intraprostatic androgen balance defines all basic functions of gland, and its safety essentially depends on testosterone blood level, therefore endogenic testosterone level it is possible to consider as universal predictor of prostata metabolic homeostasis disorders, leading to decrease in bactericidal function of gland and infections. This author’s concept allows to consider correction of an adverse hormonal and metabolic background on which the clinical picture of a chronic prostatitis (first of all, deficiency of sexual hormones as pathogenetic therapy of all infectious chronic prostatitises against which realisation of effects of antibacterial therapy is essentially facilitated is developed or last is not so necessary, to what own clinical supervision resulted in article testify. Such interdisciplinary approach will lead

  15. Androgen signaling promotes translation of TMEFF2 in prostate cancer cells via phosphorylation of the α subunit of the translation initiation factor 2.

    Directory of Open Access Journals (Sweden)

    Ryan F Overcash

    Full Text Available The type I transmembrane protein with epidermal growth factor and two follistatin motifs 2 (TMEFF2, is expressed mainly in brain and prostate. Expression of TMEFF2 is deregulated in prostate cancer, suggesting a role in this disease, but the molecular mechanism(s involved in this effect are not clear. Although androgens promote tmeff2 transcription, androgen delivery to castrated animals carrying CWR22 xenografts increases TMEFF2 protein levels in the absence of mRNA changes, suggesting that TMEFF2 may also be post-transcriptionally regulated. Here we show that translation of TMEFF2 is regulated by androgens. Addition of physiological concentrations of dihydrotestosterone (DHT to prostate cancer cell lines increases translation of endogenous TMEFF2 or transfected TMEFF2-Luciferase fusions, and this effect requires the presence of upstream open reading frames (uORFs in the 5'-untranslated region (5'-UTR of TMEFF2. Using chemical and siRNA inhibition of the androgen receptor (AR, we show that the androgen effect on TMEFF2 translation is mediated by the AR. Importantly, DHT also promotes phosphorylation of the α subunit of the translation initiation factor 2 (eIF2α in an AR-dependent manner, paralleling the effect on TMEFF2 translation. Moreover, endoplasmic reticulum (ER stress conditions, which promote eIF2α phosphorylation, also stimulate TMEFF2 translation. These results indicate that androgen signaling promotes eIF2α phosphorylation and subsequent translation of TMEFF2 via a mechanism that requires uORFs in the 5'-UTR of TMEFF2.

  16. Multiple roles for UDP-glucuronosyltransferase (UGT)2B15 and UGT2B17 enzymes in androgen metabolism and prostate cancer evolution.

    Science.gov (United States)

    Gauthier-Landry, Louis; Bélanger, Alain; Barbier, Olivier

    2015-01-01

    In the prostate, approximately 50% of androgens are from adrenal steroids, mainly dehydroepiandrosterone (DHEA), its sulfate and androstenedione. These compounds are converted first into testosterone, and then into the active hormone dihydrotestosterone (DHT). After having activated the androgen receptor (AR), DHT is reduced into androstane-3α-DIOL (3α-DIOL) and androsterone (ADT), which are subsequently converted into 2 inactive and easily excretable metabolites: 3α-DIOL-17glucuronide (3α-DIOL-17G) and ADT-3glucuronide (ADT-3G). The formation of these last derivatives through the glucuronidation reaction involves 2 UDP-glucuronosyltransferase (UGT) enzymes, namely UGT2B15 and UGT2B17. The present review article aims at providing a comprehensive view of the physiological and pharmacological importance of these 2 enzymes for the control of androgen homeostasis. We will resume: (i) how UGT2B15 and UGT2B17 contribute to androgen elimination; (ii) how their glucuronidation capacity influences the androgen signaling pathway in prostate cells; (iii) how they contribute to the anti-proliferative properties of AR antagonists in prostate cancer cells; and (iv) how AR and its spliced variants regulate the UGT2B15 and/or UGT2B17 genes expression. Finally, whether the unexploited AR-UGT axis could serve as a prognostic maker or a pharmacological target for novel therapeutics in the treatment of prostate cancer is also discussed. This article is part of a special issue entitled 'Essential role of DHEA'. Copyright © 2014 Elsevier Ltd. All rights reserved.

  17. Course and Predictors of Cognitive Function in Patients With Prostate Cancer Receiving Androgen-Deprivation Therapy: A Controlled Comparison

    Science.gov (United States)

    Gonzalez, Brian D.; Jim, Heather S.L.; Booth-Jones, Margaret; Small, Brent J.; Sutton, Steven K.; Lin, Hui-Yi; Park, Jong Y.; Spiess, Philippe E.; Fishman, Mayer N.; Jacobsen, Paul B.

    2015-01-01

    Purpose Men receiving androgen-deprivation therapy (ADT) for prostate cancer may be at risk for cognitive impairment; however, evidence is mixed in the existing literature. Our study examined the impact of ADT on impaired cognitive performance and explored potential demographic and genetic predictors of impaired performance. Patients and Methods Patients with prostate cancer were assessed before or within 21 days of starting ADT (n = 58) and 6 and 12 months later. Age- and education-matched patients with prostate cancer treated with prostatectomy only (n = 84) and men without prostate cancer (n = 88) were assessed at similar intervals. Participants provided baseline blood samples for genotyping. Mean-level cognitive performance was compared using mixed models; cognitive impairment was compared using generalized estimating equations. Results ADT recipients demonstrated higher rates of impaired cognitive performance over time relative to all controls (P = .01). Groups did not differ at baseline (P > .05); however, ADT recipients were more likely to demonstrate impaired performance within 6 and 12 months (P for both comparisons < .05). Baseline age, cognitive reserve, depressive symptoms, fatigue, and hot flash interference did not moderate the impact of ADT on impaired cognitive performance (P for all comparisons ≥ .09). In exploratory genetic analyses, GNB3 single-nucleotide polymorphism rs1047776 was associated with increased rates of impaired performance over time in the ADT group (P < .001). Conclusion Men treated with ADT were more likely to demonstrate impaired cognitive performance within 6 months after starting ADT relative to matched controls and to continue to do so within 12 months after starting ADT. If confirmed, findings may have implications for patient education regarding the risks and benefits of ADT. PMID:25964245

  18. Associations between statin use and progression in men with prostate cancer treated with primary androgen deprivation therapy

    DEFF Research Database (Denmark)

    Mikkelsen, Marta Kramer; Thomsen, Frederik Birkebæk; Berg, Kasper Drimer

    2017-01-01

    INTRODUCTION: In several observational studies, statin use has been associated with reduced risk of progression and mortality in men with prostate cancer (PCa). The study aim was to investigate the association between statin use at time of PCa diagnosis and time to PCa progression in men...... with advanced or metastatic PCa receiving androgen deprivation therapy (ADT) as primary treatment. PATIENTS AND METHODS: The study population consisted of all men receiving ADT as primary therapy at two Danish Urological Departments in 2007-2013. The primary outcome was time to progression defined as castration...... between statin use and risk of progression, HR 0.98 (95% CI: 0.72-1.32). In competing risk analyses the 5-year cumulative incidence of progression was 55% (95% CI: 46-64%) for statin users and 62% (95% CI: 57-67%) for non-statin users, p = 0.11. CONCLUSION: In the current study, statin use at time of PCa...

  19. Met-Independent Hepatocyte Growth Factor-mediated regulation of cell adhesion in human prostate cancer cells

    Directory of Open Access Journals (Sweden)

    Davis Rodney

    2006-07-01

    Full Text Available Abstract Background Prostate cancer cells communicate reciprocally with the stromal cells surrounding them, inside the prostate, and after metastasis, within the bone. Each tissue secretes factors for interpretation by the other. One stromally-derived factor, Hepatocyte Growth Factor (HGF, was found twenty years ago to regulate invasion and growth of carcinoma cells. Working with the LNCaP prostate cancer progression model, we found that these cells could respond to HGF stimulation, even in the absence of Met, the only known HGF receptor. The new HGF binding partner we find on the cell surface may help to clarify conflicts in the past literature about Met expression and HGF response in cancer cells. Methods We searched for Met or any HGF binding partner on the cells of the PC3 and LNCaP prostate cancer cell models, using HGF immobilized on agarose beads. By using mass spectrometry analyses and sequencing we have identified nucleolin protein as a novel HGF binding partner. Antibodies against nucleolin (or HGF were able to ameliorate the stimulatory effects of HGF on met-negative prostate cancer cells. Western blots, RT-PCR, and immunohistochemistry were used to assess nucleolin levels during prostate cancer progression in both LNCaP and PC3 models. Results We have identified HGF as a major signaling component of prostate stromal-conditioned media (SCM and have implicated the protein nucleolin in HGF signal reception by the LNCaP model prostate cancer cells. Antibodies that silence either HGF (in SCM or nucleolin (on the cell surfaces eliminate the adhesion-stimulatory effects of the SCM. Likewise, addition of purified HGF to control media mimics the action of SCM. C4-2, an LNCaP lineage-derived, androgen-independent human prostate cancer cell line, responds to HGF in a concentration-dependent manner by increasing its adhesion and reducing its migration on laminin substratum. These HGF effects are not due to shifts in the expression levels of

  20. Met-Independent Hepatocyte Growth Factor-mediated regulation of cell adhesion in human prostate cancer cells

    International Nuclear Information System (INIS)

    Tate, Amanda; Isotani, Shuji; Bradley, Michael J; Sikes, Robert A; Davis, Rodney; Chung, Leland WK; Edlund, Magnus

    2006-01-01

    Prostate cancer cells communicate reciprocally with the stromal cells surrounding them, inside the prostate, and after metastasis, within the bone. Each tissue secretes factors for interpretation by the other. One stromally-derived factor, Hepatocyte Growth Factor (HGF), was found twenty years ago to regulate invasion and growth of carcinoma cells. Working with the LNCaP prostate cancer progression model, we found that these cells could respond to HGF stimulation, even in the absence of Met, the only known HGF receptor. The new HGF binding partner we find on the cell surface may help to clarify conflicts in the past literature about Met expression and HGF response in cancer cells. We searched for Met or any HGF binding partner on the cells of the PC3 and LNCaP prostate cancer cell models, using HGF immobilized on agarose beads. By using mass spectrometry analyses and sequencing we have identified nucleolin protein as a novel HGF binding partner. Antibodies against nucleolin (or HGF) were able to ameliorate the stimulatory effects of HGF on met-negative prostate cancer cells. Western blots, RT-PCR, and immunohistochemistry were used to assess nucleolin levels during prostate cancer progression in both LNCaP and PC3 models. We have identified HGF as a major signaling component of prostate stromal-conditioned media (SCM) and have implicated the protein nucleolin in HGF signal reception by the LNCaP model prostate cancer cells. Antibodies that silence either HGF (in SCM) or nucleolin (on the cell surfaces) eliminate the adhesion-stimulatory effects of the SCM. Likewise, addition of purified HGF to control media mimics the action of SCM. C4-2, an LNCaP lineage-derived, androgen-independent human prostate cancer cell line, responds to HGF in a concentration-dependent manner by increasing its adhesion and reducing its migration on laminin substratum. These HGF effects are not due to shifts in the expression levels of laminin-binding integrins, nor can they be linked to

  1. Androgen deprivation therapy's impact on the mood of prostate cancer patients as perceived by patients and the partners of patients.

    Science.gov (United States)

    Van Dam, Dexter; Wassersug, Richard J; Hamilton, Lisa Dawn

    2016-07-01

    To assess the relationship between of androgen deprivation therapy (ADT) and the mood of prostate cancer (PCa) patients and partners of PCa patients. PCa patients (n = 295) and partners of patients (n = 84) completed an online survey assessing the patients' current mood and mood prior to treatment, relationship adjustment, and sexual function. We compared men on ADT to men who received non-hormonal treatments for their PCa. Patients currently treated with ADT (n = 82) reported worsened mood as measured by the Profile of Mood States compared to those not on ADT (n = 213). The negative impact of ADT on mood, however, was reduced in older patients. Partners of patients on ADT (n = 42) reported similar declines in the patient's mood that patients reported, but to a greater degree than patient-reported levels. Our data support ADT's impact on PCa patients' mood and verify that partners concurrently see the effects. The psychological changes related to ADT can impact relationships and affect the quality of life of both PCa patients and partners. Patients and their partners are likely to benefit from being well informed about the psychological effects of androgen deprivation on men beginning ADT. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

  2. Tissue specific and androgen-regulated expression of human prostate-specific transglutaminase

    NARCIS (Netherlands)

    H.J. Dubbink (Erik Jan); N.S. Verkaik (Nicole); P.W. Faber; J. Trapman (Jan); F.H. Schröder (Fritz); J.C. Romijn (Johannes)

    1996-01-01

    textabstractTransglutaminases (TGases) are calcium-dependent enzymes catalysing the post-translational cross-linking of proteins. In the prostate at least two TGases are present, the ubiquitously expressed tissue-type TGase (TGC), and a prostate-restricted TGase (TGP).

  3. (Radiolabeled androgens and progestins as imaging agents for tumors of the prostate and breast)

    Energy Technology Data Exchange (ETDEWEB)

    Katzenellenbogen, J.A.

    1991-01-01

    The specific aims of the previous grant application can be summarized as follows: Synthesize fluorine-substituted progestins from the following high affinity classes: R5020 (promegestone), norgestrel, RU486, and retroprogestins; Synthesize fluorine-substituted androgens from the following high affinity classes: mibolerone, R1881 (metribolone) and 2-oxometribolone; Evaluate the receptor binding and non-specific binding of these fluorosteroids by in vitro binding assays; Develop and optimize fluoride ion substitution reactions suitable for the rapid, efficient and convenient preparation of these fluorosteroids in high specific activity, F-18 labeled form; and Evaluate the target tissue uptake of the F-18 labeled androgens and progestins in experimental animals.

  4. [Radiolabeled androgens and progestins as imaging agents for tumors of the prostate and breast]. Progress report

    Energy Technology Data Exchange (ETDEWEB)

    Katzenellenbogen, J.A.

    1991-12-31

    The specific aims of the previous grant application can be summarized as follows: Synthesize fluorine-substituted progestins from the following high affinity classes: R5020 (promegestone), norgestrel, RU486, and retroprogestins; Synthesize fluorine-substituted androgens from the following high affinity classes: mibolerone, R1881 (metribolone) and 2-oxometribolone; Evaluate the receptor binding and non-specific binding of these fluorosteroids by in vitro binding assays; Develop and optimize fluoride ion substitution reactions suitable for the rapid, efficient and convenient preparation of these fluorosteroids in high specific activity, F-18 labeled form; and Evaluate the target tissue uptake of the F-18 labeled androgens and progestins in experimental animals.

  5. Waist circumference is an independent risk factor for prostatic hyperplasia in Taiwanese males

    Directory of Open Access Journals (Sweden)

    Hsu-Han Wang

    2011-10-01

    Conclusions: Study results showed that waist circumference ≥ 90 cm is an independent risk factor of prostatic hyperplasia in Taiwan. Men with abdominal overweight/obesity (WC ≥ 90 cm and BMI > 24 kg/m2 have a twofold risk of developing prostatic hyperplasia.

  6. Nrdp1-Mediated ErbB3 Increase During Androgen Ablation and Its Contribution to Androgen-Independence

    Science.gov (United States)

    2012-09-01

    polarization by ubiquitinating and activating transcription factor CCAAT/enhancer-binding Protein beta (C/EBPbeta). J Biol Chem 287, 26740-26748. 36...luciferase assay. LNCaP and/or C4-2, LNCaP AI, CWR22Rv1, CWR22R1 cells were transfected with 2 µg of pGL3-hPSA-luc and β- galactosidase with or without co...normalized to β- galactosidase measured by a colorimentric assay and represent an average of 3 independent experiments with data presented as relative

  7. ROR-γ drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer.

    Science.gov (United States)

    Wang, Junjian; Zou, June X; Xue, Xiaoqian; Cai, Demin; Zhang, Yan; Duan, Zhijian; Xiang, Qiuping; Yang, Joy C; Louie, Maggie C; Borowsky, Alexander D; Gao, Allen C; Evans, Christopher P; Lam, Kit S; Xu, Jianzhen; Kung, Hsing-Jien; Evans, Ronald M; Xu, Yong; Chen, Hong-Wu

    2016-05-01

    The androgen receptor (AR) is overexpressed and hyperactivated in human castration-resistant prostate cancer (CRPC). However, the determinants of AR overexpression in CRPC are poorly defined. Here we show that retinoic acid receptor-related orphan receptor γ (ROR-γ) is overexpressed and amplified in metastatic CRPC tumors, and that ROR-γ drives AR expression in the tumors. ROR-γ recruits nuclear receptor coactivator 1 and 3 (NCOA1 and NCOA3, also known as SRC-1 and SRC-3) to an AR-ROR response element (RORE) to stimulate AR gene transcription. ROR-γ antagonists suppress the expression of both AR and its variant AR-V7 in prostate cancer (PCa) cell lines and tumors. ROR-γ antagonists also markedly diminish genome-wide AR binding, H3K27ac abundance and expression of the AR target gene network. Finally, ROR-γ antagonists suppressed tumor growth in multiple AR-expressing, but not AR-negative, xenograft PCa models, and they effectively sensitized CRPC tumors to enzalutamide, without overt toxicity, in mice. Taken together, these results establish ROR-γ as a key player in CRPC by acting upstream of AR and as a potential therapeutic target for advanced PCa.

  8. Multimodal therapy for locally advanced prostate cancer: the roles of radiotherapy, androgen deprivation therapy, and their combination

    International Nuclear Information System (INIS)

    Lee, Sung Uk; Cho, Kwan Ho

    2017-01-01

    Locally advanced prostate cancer (LAPC) is defined as histologically proven T3–4 prostatic adenocarcinoma. In this review, we define the individual roles of radiotherapy (RT), short-term (ST-) and long-term (LT-) androgen deprivation therapy (ADT), and their combination in multimodal therapy for LAPC. Despite limitations in comparing the clinical outcomes among published papers, in the present study, a trend of 10-year clinical outcomes was roughly estimated by calculating the average rates weighted by the cohort number. With RT alone, the following rates were estimated: 87% biochemical failure, 34% local failure (LF), 48% distant metastasis (DM), 38% overall survival (OS), and 27% disease-specific mortality (DSM). Those associated with ADT alone were 74% BCF, 54% OS, and 25% DSM, which appeared to be better than those of RT alone. The addition of ADT to RT produced a notable local and systemic effect, regardless of ST- or LT-ADT. The LF rate decreased from 34% with RT alone to 21% with ST-ADT and further to 15% with LT-ADT. The DM and DSM rates also showed a similar trend among RT alone, RT+ST-ADT, and RT+LT-ADT. The combination of RT+LT-ADT resulted in the best long-term clinical outcomes, indicating that both RT and ADT are important parts of multimodal therapy

  9. Multimodal therapy for locally advanced prostate cancer: the roles of radiotherapy, androgen deprivation therapy, and their combination

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Sung Uk; Cho, Kwan Ho [The Proton Therapy Center, Research Institute and Hospital, National Cancer Center, Goyang (Korea, Republic of)

    2017-09-15

    Locally advanced prostate cancer (LAPC) is defined as histologically proven T3–4 prostatic adenocarcinoma. In this review, we define the individual roles of radiotherapy (RT), short-term (ST-) and long-term (LT-) androgen deprivation therapy (ADT), and their combination in multimodal therapy for LAPC. Despite limitations in comparing the clinical outcomes among published papers, in the present study, a trend of 10-year clinical outcomes was roughly estimated by calculating the average rates weighted by the cohort number. With RT alone, the following rates were estimated: 87% biochemical failure, 34% local failure (LF), 48% distant metastasis (DM), 38% overall survival (OS), and 27% disease-specific mortality (DSM). Those associated with ADT alone were 74% BCF, 54% OS, and 25% DSM, which appeared to be better than those of RT alone. The addition of ADT to RT produced a notable local and systemic effect, regardless of ST- or LT-ADT. The LF rate decreased from 34% with RT alone to 21% with ST-ADT and further to 15% with LT-ADT. The DM and DSM rates also showed a similar trend among RT alone, RT+ST-ADT, and RT+LT-ADT. The combination of RT+LT-ADT resulted in the best long-term clinical outcomes, indicating that both RT and ADT are important parts of multimodal therapy.

  10. Phase II study of neoadjuvant androgen deprivation followed by external-beam radiotherapy with 9 months of androgen deprivation for intermediate- to high-risk localized prostate cancer.

    Science.gov (United States)

    Heymann, Jonas J; Benson, Mitchell C; O'Toole, Kathleen M; Malyszko, Bozena; Brody, Rachel; Vecchio, Darleen; Schiff, Peter B; Mansukhani, Mahesh M; Ennis, Ronald D

    2007-01-01

    To evaluate the toxicity and efficacy of individualized neoadjuvant androgen deprivation (AD) to maximal response followed by external beam radiotherapy (RT) with continued AD for a total of 9 months in a prospective phase II trial. One hundred twenty-three patients received a total of 9 months of flutamide and luprolide combined with RT. RT initiation was individualized to begin after maximum response to AD as assessed by monthly digital rectal examination and prostate-specific antigen (PSA). The neoadjuvant phase was restricted to no more than 6 months. Median time to initiation of RT was 4.7 months. Indications to begin RT (and their rates) were undetectable PSA (28%), PSA unchanged from one month to the next (46%), PSA rising from one month to the next (10%), 6 months of AD (14%), and other (2%). Five-year outcomes were biochemical disease-free survival, (DFS) 63% +/- 7%; clinical DFS, 75% +/- 5%; cancer-specific survival, 99% +/- 1%; and overall survival, 89% +/- 3%. Patients initiating RT after 6 months of AD had significantly lower biochemical and clinical DFS. Those patients whose testosterone recovered to normal after completion of AD had a significantly superior survival rate. Of those patients potent before treatment, 65% remained so at last follow-up. The combination of 9 months of AD and RT, with initiation of RT individualized on the basis of maximum response to AD, achieves disease control rates comparable with past studies, while preserving potency in many patients. Further studies are warranted to determine the optimal combination of AD and RT in this patient population.

  11. Prognostic significance of Gleason score 7 (3+4 and Gleason score 7 (4+3 in prostatic adenocarcinoma in relation to clinical stage, androgen tissue status and degree of neuroendocrine differentiation

    Directory of Open Access Journals (Sweden)

    Mijović M.

    2014-01-01

    Full Text Available Prognosis and choice of treatment of adenocarcinoma of the prostate (ADCP directly depend on the numerous of predictive factors, among which the most important are summary histological tumor grade (Gleason score, which is the sum of the first and second dominant histological grade and clinical stage. According to recent research these factors include androgen tissue status and degree of neuroendocrine differentiation. The importance of the first and second dominant histological grade becomes particularly important in ADCP Gleason score 7. Tumors with worse prognosis considered to be ADCP of higher Gleason score, the advanced clinical stage, androgen independent tumors and tumors that show a higher degree of neuroendocrine differentiation. The aim of the study was to determine the predictive significance of ADCP Gleason score 7 (3+4 and ADCP Gleason score 7 (4+3 in relation to clinical stage, androgen tissue status and degree of focal neuroendocrine differentiation. The study included 33 ADCP of Gleason score 7,26 (78.79% ADCP 7 (3+4 and 7 (21.21% ADCP 7 (4+3. All tumors are most often diagnosed with stage D2, when there are already distant metastases. ADCP of Gleason score 7 (4+3 were diagnosed more often at this stage, among them there are more androgen independent tumors and they show a greater degree of focal neuroendocrine differentiation. All the results are in accordance with data from the literature suggesting that ADCP of Gleason score 7 (4+3 have a worse prognosis than ADCP of Gleason score 7 (3 +4.

  12. Immunohistochemical expression of heat shock proteins, p63 and androgen receptor in benign prostatic hyperplasia and prostatic carcinoma in the dog.

    Science.gov (United States)

    Romanucci, M; Frattone, L; Ciccarelli, A; Bongiovanni, L; Malatesta, D; Benazzi, C; Brachelente, C; Della Salda, L

    2016-12-01

    This study compared heat shock proteins Hsp60, Hsp72 and Hsp73, along with p63 and androgen receptor (AR) immunoexpression between 16 cases of benign prostatic hyperplasia (BPH) and 11 prostatic carcinomas (PCa) in dogs. The proportion of Hsp60-positive cells was higher in PCa compared with BPH (P = 0.033), whereas the frequency and intensity of Hsp73 immunostaining did not differ significantly between the two groups. Hsp72-immunostained nuclei formed a discontinuous layer along the basement membrane in BPH, whereas cells in this layer in PCa were negative or weakly positive. Hsp72 nuclear score showed significant positive associations with both p63 (P = 0.016) and AR (P = 0.009) scores. Double immunofluorescence revealed Hsp72-p63 and Hsp72-AR co-expressions in basal cell nuclei. Aberrant cytoplasmic p63 immunolabelling was observed in 3 of 11 PCa cases. These results suggest a role of the combined expression of Hsp72, p63 and AR in basal epithelial cells in canine BPH and PCa. © 2014 John Wiley & Sons Ltd.

  13. A randomized controlled trial on the effectiveness of strength training on clinical and muscle cellular outcomes in patients with prostate cancer during androgen deprivation therapy: rationale and design.

    Science.gov (United States)

    Thorsen, Lene; Nilsen, Tormod S; Raastad, Truls; Courneya, Kerry S; Skovlund, Eva; Fosså, Sophie D

    2012-03-29

    Studies indicate that strength training has beneficial effects on clinical health outcomes in prostate cancer patients during androgen deprivation therapy. However, randomized controlled trials are needed to scientifically determine the effectiveness of strength training on the muscle cell level. Furthermore, close examination of the feasibility of a high-load strength training program is warranted. The Physical Exercise and Prostate Cancer (PEPC) trial is designed to determine the effectiveness of strength training on clinical and muscle cellular outcomes in non-metastatic prostate cancer patients after high-dose radiotherapy and during ongoing androgen deprivation therapy. Patients receiving androgen deprivation therapy for 9-36 months combined with external high-dose radiotherapy for locally advanced prostate cancer are randomized to an exercise intervention group that receives a 16 week high-load strength training program or a control group that is encouraged to maintain their habitual activity level. In both arms, androgen deprivation therapy is continued until the end of the intervention period.Clinical outcomes are body composition (lean body mass, bone mineral density and fat mass) measured by Dual-energy X-ray Absorptiometry, serological outcomes, physical functioning (muscle strength and cardio-respiratory fitness) assessed with physical tests and psycho-social functioning (mental health, fatigue and health-related quality of life) assessed by questionnaires. Muscle cellular outcomes are a) muscle fiber size b) regulators of muscle fiber size (number of myonuclei per muscle fiber, number of satellite cells per muscle fiber, number of satellite cells and myonuclei positive for androgen receptors and proteins involved in muscle protein degradation and muscle hypertrophy) and c) regulators of muscle fiber function such as proteins involved in cellular stress and mitochondrial function. Muscle cellular outcomes are measured on muscle cross sections and muscle

  14. A randomized controlled trial on the effectiveness of strength training on clinical and muscle cellular outcomes in patients with prostate cancer during androgen deprivation therapy: rationale and design

    Directory of Open Access Journals (Sweden)

    Thorsen Lene

    2012-03-01

    Full Text Available Abstract Background Studies indicate that strength training has beneficial effects on clinical health outcomes in prostate cancer patients during androgen deprivation therapy. However, randomized controlled trials are needed to scientifically determine the effectiveness of strength training on the muscle cell level. Furthermore, close examination of the feasibility of a high-load strength training program is warranted. The Physical Exercise and Prostate Cancer (PEPC trial is designed to determine the effectiveness of strength training on clinical and muscle cellular outcomes in non-metastatic prostate cancer patients after high-dose radiotherapy and during ongoing androgen deprivation therapy. Methods/design Patients receiving androgen deprivation therapy for 9-36 months combined with external high-dose radiotherapy for locally advanced prostate cancer are randomized to an exercise intervention group that receives a 16 week high-load strength training program or a control group that is encouraged to maintain their habitual activity level. In both arms, androgen deprivation therapy is continued until the end of the intervention period. Clinical outcomes are body composition (lean body mass, bone mineral density and fat mass measured by Dual-energy X-ray Absorptiometry, serological outcomes, physical functioning (muscle strength and cardio-respiratory fitness assessed with physical tests and psycho-social functioning (mental health, fatigue and health-related quality of life assessed by questionnaires. Muscle cellular outcomes are a muscle fiber size b regulators of muscle fiber size (number of myonuclei per muscle fiber, number of satellite cells per muscle fiber, number of satellite cells and myonuclei positive for androgen receptors and proteins involved in muscle protein degradation and muscle hypertrophy and c regulators of muscle fiber function such as proteins involved in cellular stress and mitochondrial function. Muscle cellular outcomes

  15. Nutrition therapy with high intensity interval training to improve prostate cancer-related fatigue in men on androgen deprivation therapy: a study protocol.

    Science.gov (United States)

    Baguley, Brenton J; Skinner, Tina L; Leveritt, Michael D; Wright, Olivia R L

    2017-01-03

    Cancer-related fatigue is one of the most prevalent, prolonged and distressing side effects of prostate cancer treatment with androgen deprivation therapy. Preliminary evidence suggests natural therapies such as nutrition therapy and structured exercise prescription can reduce symptoms of cancer-related fatigue. Men appear to change their habitual dietary patterns after prostate cancer diagnosis, yet prostate-specific dietary guidelines provide limited support for managing adverse side effects of treatment. The exercise literature has shown high intensity interval training can improve various aspects of health that are typically impaired with androgen deprivation therapy; however exercise at this intensity is yet to be conducted in men with prostate cancer. The purpose of this study is to examine the effects of nutrition therapy beyond the current healthy eating guidelines with high intensity interval training for managing cancer-related fatigue in men with prostate cancer treated with androgen deprivation therapy. This is a two-arm randomized control trial of 116 men with prostate cancer and survivors treated with androgen deprivation therapy. Participants will be randomized to either the intervention group i.e. nutrition therapy and high intensity interval training, or usual care. The intervention group will receive 20 weeks of individualized nutrition therapy from an Accredited Practising Dietitian, and high intensity interval training (from weeks 12-20 of the intervention) from an Accredited Exercise Physiologist. The usual care group will maintain their standard treatment regimen over the 20 weeks. Both groups will undertake primary and secondary outcome testing at baseline, week 8, 12, and 20; testing includes questionnaires of fatigue and quality of life, objective measures of body composition, muscular strength, cardiorespiratory fitness, biomarkers for disease progression, as well as dietary analysis. The primary outcomes for this trial are measures of

  16. Biological aspects of the potential interaction between androgen suppression and radiation therapy

    International Nuclear Information System (INIS)

    Zietman, Anthony L.

    1996-01-01

    It is a basic axiom of radiotherapy that the radiation dose required for tumor eradication increases with increasing tumor volume. These Patterns of Care Studies and prospective studies using rebiopsy have shown that this holds true for prostate cancer as well. Despite our best endeavors with conventional dose, there remains a substantial element of local failure following radiotherapy, and this is T-stage related. Unlikely many other solid tumors, a convenient method of volume reduction exists for prostate carcinoma. Approximately 90% demonstrate shrinkage following androgen suppression, an effect that is more pronounced at the primary site than metastatic sites. Transrectal ultrasound studies have shown a median of 40% prostatic tumor volume reduction after 3-4 months of androgen suppression. With more protracted androgen suppression the shrinkage progresses and a small minority of patients may actually have a complete response determined pathologically. Animal models demonstrate clearly that the TCD 50 of androgen dependent tumors may be decreased by prior androgen depression. This effect is most pronounced if radiation is deferred until the time of maximal tumor regression. The advantage is lost if the tumor is allowed to regrow in an androgen independent fashion to its original volume. It is not clear whether this benefit of neoadjuvant androgen suppression results solely from volume shrinkage. The potential for synergy exists as both radiation and androgen suppression have an element of apoptosis as a common pathway of cell death. Although apoptosis is certainly the major cause of cell death from androgen suppression its' contribution to radiation cell kill in prostatic adenocarcinomas is yet to be evaluated. If the two effects are additive and not synergistic, then sequence should be unimportant. Animal models, however, demonstrate that the TCD 50 of androgen dependent tumors is not significantly reduced by adjuvant androgen suppression. Human data is still

  17. Avoidance of androgen deprivation therapy in radiorecurrent prostate cancer as a clinically meaningful endpoint for salvage cryoablation.

    Science.gov (United States)

    Ginsburg, Kevin B; Elshafei, Ahmed; Yu, Changhong; Jones, J Stephen; Cher, Michael L

    2017-10-01

    To investigate the ability of salvage cryoablation of the prostate (SCAP) to delay the need for androgen deprivation therapy (ADT) in local recurrence after radiation therapy to the prostate using the Cryo-On-Line Database (COLD) registry. The COLD registry is comprised of a combination of retrospectively and prospectively collected data on patients undergoing primary and SCAP. Patients with local recurrence after radiation therapy were identified. Kaplan-Meier analysis was used to calculate ADT-free survival. We identified 898 patients that have undergone SCAP in the COLD registry. Overall, the calculated 5-year ADT-free survival probability was 0.713. When stratified by D'Amico risk group, 264 high-risk patients (71.9%), 234 intermediate-risk (86.7%),and 228 low-risk (87.7%) were free of ADT post-SCAP. This correlates with a 5-year ADT-free survival of 60.7, 73.9, and 82.4%, respectively. Patients with post-SCAP PSA nadir of <0.2 ng/mL had a 5 year ADT-free survival of 87.1% compared to 48.7% with a PSA nadir ≥0.2 ng/mL. Pre-operative ADT use or full versus partial gland SCAP did not have an effect on ADT use post-operatively. In 118 (55.4%) of patients with post-operative biochemical recurrence, ADT was not used. For patients with local recurrence after radiation, SCAP is an option that provides a high chance of avoiding or delaying ADT. The potential to delay ADT and its associated side effects should be a part of counseling sessions with the patient when discussing treatment options for locally recurrent prostate cancer after radiation. Avoidance of ADT is more clinically relevant than PSA elevation. © 2017 Wiley Periodicals, Inc.

  18. Recognizing False Biochemical Failure Calls After Radiation With or Without Neo-Adjuvant Androgen Deprivation for Prostate Cancer

    International Nuclear Information System (INIS)

    Denham, James W.; Kumar, Mahesh; Gleeson, Paul S.; Lamb, David S.; Joseph, David FRANZCR.; Atkinson, Chris FRANZCR.; Matthews, John FRANZCR.; Tai, K.-H.; Spry, Nigel A.; Christie, David; Turner, Sandra FRANZCR.; Greer, Peter B.; D'Este, Catherine; Steigler, Allison

    2009-01-01

    Purpose: We studied prostate-specific antigen (PSA) changes after radiation with or without neoadjuvant androgen deprivation to determine posttreatment PSA scenarios in which false-positive biochemical failures (FPBF) are most likely to occur. Methods and Materials: In the Trans-Tasman Radiation Oncology 96.01 Group trial, patients with T2b, 2c, 3, 4 N0 prostate cancer were randomized to 3 or 6 months goserelin and flutamide (STAD) before and during 66 Gy to the prostate and seminal vesicles (XRT) or to XRT alone. Piecewise longitudinal changes in PSA before relapse were characterized and quantified to determine which might cause FPBF calls. Results: Between 1996 and 2000, 802 eligible patients were randomized. Of these, 492 met the criteria for American Society for Therapeutic Radiology and Oncology (ASTRO) failure and 467 for Phoenix failure. Seventy-seven ASTRO fails and 39 Phoenix fails were deemed false positives (FPs). The majority of FPBFs were associated with the 'plateauing' in PSA values that follow posttreatment nadir. FPBFs were particularly common in men treated with STAD, in whom small, consecutive PSA rises before or during this phenomenon triggered 56 FP ASTRO fail calls. In these men, the Phoenix fail criteria triggered only 15 FPBF calls. However, the Phoenix criteria were more vulnerable than ASTRO to short-term isolated PSA rises during plateau, which resulted in 15 Phoenix fail calls but only 3 FP ASTRO fails. Conclusions: The Phoenix definition avoided 50% of FPBF calls that occurred with the ASTRO definition. Failures should be confirmed by further PSA rises before investigation and treatment is considered.

  19. Patterns of androgen deprivation therapies among men diagnosed with localised prostate cancer: a population-based study.

    Science.gov (United States)

    Lycken, Magdalena; Garmo, Hans; Adolfsson, Jan; Stattin, Pär; Holmberg, Lars; Bill-Axelson, Anna

    2014-07-01

    Many men diagnosed with localised prostate cancer will eventually be treated with androgen deprivation therapy (ADT). ADT is associated with adverse effects and its timing is controversial. Data on patterns of use are scarce. We describe patterns of ADT use, defined as castration (medical and surgical) or antiandrogen monotherapy initiated after primary treatment, in a population-based cohort. Data were extracted from the population-based Prostate Cancer data Base Sweden (PCBaSe). Totally 45,147 men diagnosed between 1997 and 2009 with clinical stage T1-2, N0-NX, M0-MX and prostate specific antigen (PSA)<50ng/ml without primary ADT were included. Outcomes in the period 2006 through 2010 were analysed using a period analysis approach. The cumulative incidence of castration at 10years after diagnosis was 11.6% (95% confidence interval (CI), 11.0-12.2%). The corresponding proportion of antiandrogen monotherapy was 10.8% (95% CI, 10.2-11.4%). Castration was the dominant therapy among men on deferred treatment. The probability of receiving castration rather than antiandrogen monotherapy increased with age. Estimated median durations of castration ranged from 4years in the deferred treatment high-risk group to 17years in the prostatectomy low-risk group. The main limitation was the lack of information on progression to metastatic disease and PSA at the time for initiation of ADT. When initiated early after curative treatment, the duration of castration can be decades. The findings indicate that more accurate tools are necessary to guide which men should be selected for ADT as secondary treatment. Copyright © 2014 Elsevier Ltd. All rights reserved.

  20. Sleep disturbance in men receiving androgen deprivation therapy for prostate cancer: The role of hot flashes and nocturia.

    Science.gov (United States)

    Gonzalez, Brian D; Small, Brent J; Cases, Mallory G; Williams, Noelle L; Fishman, Mayer N; Jacobsen, Paul B; Jim, Heather S L

    2018-02-01

    Patients with prostate cancer receiving androgen deprivation therapy (ADT) are at risk of sleep disturbance; however, to the authors' knowledge, the mechanisms by which ADT may affect sleep are not well understood. The current study compared objective and subjective sleep disturbance in ADT recipients and controls and examined whether sleep disturbance in ADT recipients is attributable to the influence of ADT on hot flashes and nocturia. Patients with prostate cancer were assessed before or within 1 month after the initiation of ADT as well as 6 months and 12 months later (78 patients). Patients with prostate cancer were treated with prostatectomy only (99 patients) and men with no history of cancer (108 men) were assessed at similar intervals. Participants self-reported their sleep disturbance (Insomnia Severity Index) and interference from hot flashes (Hot Flash Related Daily Interference Scale). One hundred participants also wore actigraphs for 3 days at the 6-month assessment to measure objective sleep disturbance and reported their nocturia frequency. ADT recipients reported worse sleep disturbance, higher rates of clinically significant sleep disturbance, and greater hot flash interference than controls (Ps≤.03). In cross-sectional analyses among those with actigraphy data, ADT recipients had greater objective sleep disturbance and more episodes of nocturia (Pssleep disturbance was partly attributable to nocturia and hot flashes (Pssleep may be partly explained by nocturia and hot flash interference. Future studies should examine behavioral and pharmacologic interventions to address these symptoms among ADT recipients. Cancer 2018;124:499-506. © 2017 American Cancer Society. © 2017 American Cancer Society.

  1. Identification of a RhoA- and SRF-dependent mechanism of androgen action that is associated with prostate cancer progression.

    Science.gov (United States)

    Heemers, Hannelore V

    2013-04-01

    Androgen receptor (AR) action is critical for prostate cancer (CaP) progression, but is not inhibited fully by available androgen deprivation therapy (ADT). One of the limitations to current ADT is that it targets all androgen action in CaP, and other, cells irrespective of clinical relevance. The resulting off-target effects are responsible for ADT associated side effects that affect negatively a patient's quality of life. Isolation of the AR-dependent events that drive CaP progression may lead to novel forms of ADT that are at least as effective but more selective. Here, an approach is described that starts from insights in the basic mechanism(s) by which AR regulates target gene expression to identify novel drugable targets downstream of AR. Exploration of the molecular events that underlie androgen regulation of the AR-associated coregulator FHL2 led to the isolation of a novel indirect mechanism of androgen action that is mediated by the secondary transcription factor Serum Response Factor (SRF). Using a combination of oligoarray and in silico analyses, an SRF-dependent fraction of AR action was identified that is enriched in CaP tissues, is able to discriminate between benign and malignant prostate, and correlates with aggressive disease and biochemical failure. The RhoA signaling axis, a well known upstream stimulator of SRF action that harbors drugable targets, conveyed androgen-responsiveness to SRF, and was activated in CaP where it correlates with increased CaP aggressiveness and poor outcome after surgery.

  2. Humanized Androgen Receptor Mice: A Genetic Model for Differential Response to Prostate Cancer Therapy

    Science.gov (United States)

    2012-07-01

    sig- nificant in cancer . AR-R753Q is especially intriguing since as a germline mutation it underlies rat testicular feminization as well as cases of...prostate cancers . Her research is focused on novel therapeutic interventions and designs and she is funded by several peer reviewed grants. The author...Genetic Model for Differential Response to Prostate Cancer Therapy PRINCIPAL INVESTIGATOR: Diane M. Robins, Ph.D

  3. Multivalent Peptidomimetic Conjugates as Inhibitors of Androgen Receptor Function in Therapy-Resistant Prostate Cancer

    Science.gov (United States)

    2017-10-01

    Prostate Cancer PRINCIPAL INVESTIGATOR: Kent Kirshenbaum CONTRACTING ORGANIZATION: New York University New York, NY 10012 REPORT DATE: October...ADDRESS(ES) New York University 100 Washington Sq. E., Room 1001 New York, NY 10003 9. SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10...studies on MPC6 on AR. He also helped write the paper on MPC6 function and activity in prostate cancer. Funding Support: CDMRP     5 Name

  4. Hedgehog overexpression leads to the formation of prostate cancer stem cells with metastatic property irrespective of androgen receptor expression in the mouse model

    Directory of Open Access Journals (Sweden)

    Chang Chin-Pao

    2011-01-01

    Full Text Available Abstract Background Hedgehog signalling has been implicated in prostate tumorigenesis in human subjects and mouse models, but its effects on transforming normal basal/stem cells toward malignant cancer stem cells remain poorly understood. Methods We produced pCX-shh-IG mice that overexpress Hedgehog protein persistently in adult prostates, allowing for elucidation of the mechanism during prostate cancer initiation and progression. Various markers were used to characterize and confirm the transformation of normal prostate basal/stem cells into malignant cancer stem cells under the influence of Hedgehog overexpression. Results The pCX-shh-IG mice developed prostatic intraepithelial neoplasia (PIN that led to invasive and metastatic prostate cancers within 90 days. The prostate cancer was initiated through activation of P63+ basal/stem cells along with simultaneous activation of Hedgehog signalling members, suggesting that P63+/Patch1+ and P63+/Smo+ cells may serve as cancer-initiating cells and progress into malignant prostate cancer stem cells (PCSCs. In the hyperplastic lesions and tumors, the progeny of PCSCs differentiated into cells of basal-intermediate and intermediate-luminal characteristics, whereas rare ChgA+ neuroendocrine differentiation was seen. Furthermore, in the metastatic loci within lymph nodes, kidneys, and lungs, the P63+ PCSCs formed prostate-like glandular structures, characteristic of the primitive structures during early prostate development. Besides, androgen receptor (AR expression was detected heterogeneously during tumor progression. The existence of P63+/AR-, CK14+/AR- and CD44+/AR- progeny indicates direct procurement of AR- malignant cancer trait. Conclusions These data support a cancer stem cell scenario in which Hedgehog signalling plays important roles in transforming normal prostate basal/stem cells into PCSCs and in the progression of PCSCs into metastatic tumor cells.

  5. Indole-3-carbinol and 3’, 3’-diindolylmethane modulate androgen effect up-regulation on C-C chemokine ligand 2 and monocyte attraction to prostate cancer cells

    Science.gov (United States)

    Inflammation has a role in prostate tumorigenesis. Recruitment of inflammatory monocytes to the tumor site is mediated by C-C chemokine ligand 2 (CCL2) through binding to its receptor CCR2. We hypothesized that androgen could modulate CCL2 expression in hormone-responsive prostate cancer cells, and ...

  6. Effects of cypermethrin on the ligand-independent interaction between androgen receptor and steroid receptor coactivator-1

    International Nuclear Information System (INIS)

    Pan, Chen; Liu, Ya-Peng; Li, Yan-Fang; Hu, Jin-Xia; Zhang, Jin-Peng; Wang, Hong-Mei; Li, Jing; Xu, Li-Chun

    2012-01-01

    The pyrethroid insecticide, cypermethrin has been considered as an environmental anti-androgen by interfering with the androgen receptor (AR) transactivation. In order to clarify the effects of cypermethrin on the ligand-independent interaction between the AR and SRC-1, the mammalian two-hybrid assay has been developed in the study. The AR N-terminal domain 1–660 amino acid residues were subcloned into the plasmid pVP16 to construct the vector pVP16-ARNTD. The SRC-1 C-terminal domain 989–1240 amino acid residues were subcloned into the plasmid pM to construct the vector pM-SRC-1. The fusion vectors pVP16-ARNTD, pM-SRC-1 and the pG5CAT Reporter Vector were cotransfected into the CV-1 cells. The AR AF1 interacted with SRC-1 in the absence of exogenous ligand 5α-dihydrotestosterone (DHT). Furthermore, DHT did not enhance the interaction between AR AF-1 and SRC-1 at the concentrations from 10 −10 M to 10 −8 M. Cypermethrin inhibited the interaction between the AR AF1 and SRC-1, and the significant reduction was detected at the concentration of 10 −5 M. It is suggested that the interaction between the AR AF1 and SRC-1 is ligand-independent. Cypermethrin inhibits AR activity by disrupting the ligand-independent AR–SRC-1 interaction.

  7. Sunitinib Plus Androgen Deprivation and Radiation Therapy for Patients With Localized High-Risk Prostate Cancer: Results From a Multi-institutional Phase 1 Study

    Energy Technology Data Exchange (ETDEWEB)

    Corn, Paul G., E-mail: pcorn@mdanderson.org [Department of Genitourinary Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas (United States); Song, Danny Y. [Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland (United States); Heath, Elisabeth; Maier, Jordan [Karmanos Cancer Institute, Wayne State University, Detroit, Michigan (United States); Meyn, Raymond [Department of Experimental Radiation Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas (United States); Kuban, Deborah [Department of Radiation Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas (United States); DePetrillo, Thomas A. [Department of Radiation Oncology, Tufts Medical Center, Boston, Massachusetts (United States); Mathew, Paul, E-mail: pmathew@tuftsmedicalcenter.org [Department of Hematology-Oncology, Tufts Medical Center, University of Texas M. D. Anderson Cancer Center, Houston, Texas (United States)

    2013-07-01

    Purpose: To evaluate the feasibility of administering sunitinib in combination with androgen deprivation therapy and external-beam intensity modulated radiation therapy (XRT) in patients with localized high-risk prostate cancer. Methods and Materials: Seventeen men with localized adenocarcinoma of the prostate with cT2c-cT4 or Gleason 8-10 or prostate-specific antigen >20 ng/mL received initial androgen deprivation (leuprolide 22.5 mg every 12 weeks plus oral bicalutamide 50 mg daily) for 4-8 weeks before oral sunitinib 12.5, 25, or 37.5 mg daily for 4 weeks as lead-in, then concurrently with and 4 weeks after XRT (75.6 Gy in 42 fractions to prostate and seminal vesicles). A 3+3 sequential dose-escalation design was used to assess the frequency of dose-limiting toxicity (DLT) and establish a maximal tolerated dose of sunitinib. Results: Sunitinib at 12.5- and 25-mg dose levels was well tolerated. The first 4 patients enrolled at 37.5 mg experienced a DLT during lead-in, and a drug interaction between sunitinib and bicalutamide was suspected. The protocol was revised and concurrent bicalutamide omitted. Of the next 3 patients enrolled at 37.5 mg, 2 of 3 receiving concurrent therapy experienced DLTs during radiation: grade 3 diarrhea and grade 3 proctitis, respectively. Only 1 of 7 patients completed sunitinib at 37.5 mg daily, whereas 3 of 3 patients (25 mg as starting dose) and 3 of 4 patients (25 mg as reduced dose) completed therapy. Conclusions: The feasibility of combined vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor (PDGFR) inhibitor therapy, androgen deprivation, and radiation therapy for prostate cancer was established. Using a daily dosing regimen with lead-in, concurrent, and post-XRT therapy, the recommended phase 2 dose of sunitinib is 25 mg daily.

  8. SOD mimetics: A Novel Class of Androgen Receptor Inhibitors that Suppresses Castration-Resistant Growth of Prostate Cancer

    Science.gov (United States)

    Thomas, Rusha; Sharifi, Nima

    2011-01-01

    Advanced prostate cancer (PCa) is the second-leading cause of cancer-related deaths among American men. The androgen receptor (AR) is vital for PCa progression, even in the face of castrate levels of serum testosterone following androgen ablation therapy, a mainstay therapy for advanced PCa. Downregulation of superoxide dismutase 2 (SOD2), a major intracellular antioxidant enzyme, occurs progressively during PCa progression to advanced states, and is known to promote AR activity in PCa. Therefore, this study investigated the effects of SOD mimetics on AR expression and function in AR-dependent LNCaP, CWR22Rv1, and LAPC-4AD PCa cells. Treatment with Tempol, a SOD mimetic, not only lowered cellular superoxide levels, but also concomitantly attenuated AR transcriptional activity and AR target gene expression in a dose- and time-dependent manner, in the presence and absence of dihydrotestosterone, the major endogenous AR agonist. Tempol's inhibition of AR was mediated, in large part, by its ability to decrease AR protein via increased degradation, in the absence of any inhibitory effects on other nuclear receptors. Tempol's inhibitory effects on AR were also reproducible with other SOD mimetics, MnTBAP and MnTMPyP. Importantly, Tempol's effects on AR function were accompanied by significant in vitro and in vivo reduction in castration-resistant PCa survival and growth. Collectively, this study has demonstrated for the first time that SOD mimetics, by virtue of their ability to suppress AR function, may be beneficial in treating the currently incurable castration-resistant PCa in which SOD2 expression is highly suppressed. PMID:22172488

  9. Prevention of Gynecomastia and Breast Pain Caused by Androgen Deprivation Therapy in Prostate Cancer: Tamoxifen or Radiotherapy?

    Energy Technology Data Exchange (ETDEWEB)

    Arruda Viani, Gustavo, E-mail: gusviani@gmail.com [Department of Radiation Oncology, Marilia Medical School, Marilia, Sao Paulo (Brazil); Bernardes da Silva, Lucas Godoi; Stefano, Eduardo Jose [Department of Radiation Oncology, Marilia Medical School, Marilia, Sao Paulo (Brazil)

    2012-07-15

    Purpose: To determine, in a meta-analysis, whether gynecomastia and breast pain rates in men with prostate cancer treated with androgen deprivation therapy (ADT) are reduced if treated with prophylactic radiotherapy (RT) or tamoxifen (TMX). Methods and Materials: The MEDLINE, EMBASE, CANCERLIT, and Cochrane Library databases, as well as proceedings of annual meetings, were systematically searched to identify randomized, controlled studies comparing RT or TMX with observation for men with prostate cancer using ADT. Results: Six RCTs (three RT trials and three TMX trials, N = 777 patients total) were identified that met the study criteria. Pooled results from these RCTs comparing RT vs. observation showed a significant reduction in the incidence of gynecomastia and breast pain rates in patients treated with RT (odds ratio [OR] = 0.21, 95% confidence interval [CI] = 0.12-0.37, p < 0.0001, and OR = 0.34, 95% CI 0.20-0.57, p < 0.0001, respectively). Use of RT resulted in an absolute risk reduction (ARR) of 29.4% and 19.9%, with a number needed to treat (NNT) of 3.4 and 5 to avoid one case of gynecomastia and breast pain, respectively. Pooled results from trials comparing TMX vs. observation showed a statistical benefit for breast pain and gynecomastia in favor of TMX arms (OR = 0.04, 95% CI = 0.02-0.08, p < 0.0001 and OR = 0.07, 95% CI = 0.0-0.14, p < 0.00001). TMX resulted in an ARR = 64.1% and 47.6%, with an NNT of 1.56 and 2.1 to avoid one case of gynecomastia and breast pain, respectively. Considering adverse effects, TMX was 6 times more adverse effects than RT. Conclusions: Our data have shown that both TMX and RT prevented gynecomastia and breast pain in patients with prostate cancer receiving ADT for prostate cancer. Although TMX was two times more effective in preventing gynecomastia, RT should represent an effective and safe treatment option, to take into account mainly in patients with cardiovascular risk factors or thrombotic diathesis.

  10. Exercise Improves V˙O2max and Body Composition in Androgen Deprivation Therapy-treated Prostate Cancer Patients.

    Science.gov (United States)

    Wall, Bradley A; GALVãO, Daniel A; Fatehee, Naeem; Taaffe, Dennis R; Spry, Nigel; Joseph, David; Hebert, Jeffrey J; Newton, Robert U

    2017-08-01

    Prostate cancer is the most common cancer in men, and patients treated with androgen deprivation therapy (ADT) experience unfavorable changes in body composition and associated metabolic complications, which can increase the risk of cardiovascular disease. We examined the effect of a 6-month program of aerobic and resistance exercise aimed at improving body composition and cardiorespiratory health in this population. Ninety-seven men (43-90 yr) with localized prostate cancer receiving ADT were randomized to either exercise (EX, n = 50) or usual care (CON, n = 47). Supervised exercise was undertaken twice weekly at moderate to high intensity. Measures of cardiorespiratory capacity (V˙O2max), resting metabolic rate, central blood pressure, hemodynamic variables, blood markers, and body composition were assessed. There was a significant group-time interaction present for V˙O2max (P = 0.033) with a treatment effect for EX of 0.11 L·min (95% confidence interval [CI] = 0.04-0.19) (relative to body mass = 1.3 mL·kg·min, 95% CI = 0.3-2.3) and fat oxidation (P = 0.037) of 12.0 mg·min (95% CI = 2.3-21.7). Similarly, there was a significant improvement in glucose (P < 0.001) for EX of -0.5 mmol·L (95% CI = -0.8 to -0.3), with no change in prostate-specific antigen or testosterone as a result of exercise. Body composition was enhanced for EX with adjusted mean differences in lean mass (P = 0.015) of 0.8 kg (95% CI = 0.3-1.3), total fat mass (P = 0.020) of -1.1 kg (95% CI = -1.8 to -0.5), and trunk fat mass (P < 0.001) of -1.0 kg (95% CI = -1.4 to -0.6). A 6-month combined aerobic and resistance exercise program has a significant favorable effect on cardiorespiratory capacity, resting fat oxidation, glucose, and body composition despite the adverse effects of hormone suppression. Combined aerobic and resistance training should be considered a key adjuvant component in men undergoing ADT for the treatment of prostate cancer.

  11. Evaluation of urinary prostate cancer antigen-3 (PCA3) and TMPRSS2-ERG score changes when starting androgen-deprivation therapy with triptorelin 6-month formulation in patients with locally advanced and metastatic prostate cancer

    DEFF Research Database (Denmark)

    Martínez-Piñeiro, Luis; Schalken, Jack A; Cabri, Patrick

    2014-01-01

    OBJECTIVE: To assess prostate cancer antigen-3 (PCA3) and TMPRSS2-ERG scores in patients with advanced and metastatic prostate cancer at baseline and after 6 months of treatment with triptorelin 22.5 mg, and analyse these scores in patient-groups defined by different disease characteristics....... PATIENTS AND METHODS: The Triptocare study was a prospective, open-label, multicentre, single-arm, Phase III study of triptorelin 22.5 mg in men with locally advanced or metastatic prostate cancer, who were naïve to androgen-deprivation therapy (ADT). The primary objective was to model the urinary PCA3...... change at 6 months, according to baseline variables. Other outcome measures included urinary PCA3 and TMPRSS2-ERG scores and statuses, and serum testosterone and prostate-specific antigen (PSA) levels at baseline and at 1, 3 and 6 months after initiation of ADT. Safety was assessed by recording adverse...

  12. Treatment of gynecomastia in patients with prostate cancer and androgen deprivation.

    Science.gov (United States)

    Bautista-Vidal, C; Barnoiu, O; García-Galisteo, E; Gómez-Lechuga, P; Baena-González, V

    2014-01-01

    Gynecomastia, defined as benign proliferation of glandular breast tissue has a prevalence of 32% to 72% in the male. In the urology setting, it is associated to patients with prostate cancer and hormone treatment with a prevalence of 15% in the case of complete hormone blockage and 75% in monotherapy. The different options of treatment in prostate cancer have changed in recent decades. Thus, we have focused on this subject to evaluate the different therapy options of hormone manipulation induced gynecomastia in prostate cancer patients. To synthesize the available evidence on the different therapeutic options in prostate cancer patients who develop gynecomastia due to the use of nonsteroidal antiandrogens and to generate a diagnostic algorithm and treatment. Using the PICO type structured search strategy (Patient or problem, Intervention, Comparison, Outcome or result) in the data bases of PubMed-Medline and Cochrane, identification was made of the relevant studies related to the treatment of gynecomastia in Prostate Cancer patients treated with nonsteroidal antiandrogens. We have found 3 possible therapeutic options for the treatment of gynecomastia and mastodynia in patients with hormone deprivation therapy for prostate cancer. The 10Gy radiotherapy would be an option for the treatment of gynecomastia, although not all the patients need prophylactic treatment since only 50% report moderate-severe discomfort. Another option is the use of drugs such as tamoxifen 20mg/day that lead to a significant decrease in the mammary effects. Gynecomastia and mastodynia, given their high incidence, make the physical examination a fundamental tool for all patients before initiating treatment with antiandrogens. The use of tamoxifen 20mg/day is the best treatment and prevention option against gynecomastia and mastodynia, while in the case of long-course established gynecomastia, surgery is the gold standard. Copyright © 2012 AEU. Published by Elsevier Espana. All rights reserved.

  13. The impact of androgen deprivation therapy on setup errors during external beam radiation therapy for prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Onal, Cem; Dolek, Yemliha; Ozdemir, Yurday [Baskent University, Faculty of Medicine, Adana Dr. Turgut Noyan Research and Treatment Centre, Department of Radiation Oncology, Adana (Turkey)

    2017-06-15

    To determine whether setup errors during external beam radiation therapy (RT) for prostate cancer are influenced by the combination of androgen deprivation treatment (ADT) and RT. Data from 175 patients treated for prostate cancer were retrospectively analyzed. Treatment was as follows: concurrent ADT plus RT, 33 patients (19%); neoadjuvant and concurrent ADT plus RT, 91 patients (52%); RT only, 51 patients (29%). Required couch shifts without rotations were recorded for each megavoltage (MV) cone beam computed tomography (CBCT) scan, and corresponding alignment shifts were recorded as left-right (x), superior-inferior (y), and anterior-posterior (z). The nonparametric Mann-Whitney test was used to compare shifts by group. Pearson's correlation coefficient was used to measure the correlation of couch shifts between groups. Mean prostate shifts and standard deviations (SD) were calculated and pooled to obtain mean or group systematic error (M), SD of systematic error (Σ), and SD of random error (σ). No significant differences were observed in prostate shifts in any direction between the groups. Shifts on CBCT were all less than setup margins. A significant positive correlation was observed between prostate volume and the z-direction prostate shift (r = 0.19, p = 0.04), regardless of ADT group, but not between volume and x- or y-direction shifts (r = 0.04, p = 0.7; r = 0.03, p = 0.7). Random and systematic errors for all patient cohorts and ADT groups were similar. Hormone therapy given concurrently with RT was not found to significantly impact setup errors. Prostate volume was significantly correlated with shifts in the anterior-posterior direction only. (orig.) [German] Ziel war zu untersuchen, ob Konfigurationsfehler bei der externen Radiotherapie (RT) des Prostatakarzinoms durch die Kombination aus Androgendeprivationstherapie (ADT) und RT beeinflusst werden. Retrospektiv wurden die Daten von 175 wegen eines Prostatakarzinoms behandelten Patienten

  14. Survival Signaling in Prostate Cancer: Role of Androgen Receptor and Integrins in Regulating Survival

    Science.gov (United States)

    2011-01-01

    Prostate Cancer Predoctoral Training Award (W81XWH- 08-1-0058) to L.L., and the American Cancer Society (RSG-05-245- 01- CSM ) to C.K.M. Additional support...Prostate Cancer Predoctoral Training Award (W81XWH-08-1-0058) (L.E.L.), and the American Cancer Society (RSG-05-245-01- CSM ) (C.K.M). Additional...Schmittgen TD . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-ΔΔC(T)) Method. Methods 2001; 25: 402-8. 26. Sun

  15. Downregulation of androgen receptors by NaAsO2via inhibition of AKT-NF-κB and HSP90 in castration resistant prostate cancer.

    Science.gov (United States)

    Kim, Yunlim; Park, Sang Eun; Moon, Jeong-Weon; Kim, Bong-Min; Kim, Ha-Gyeong; Jeong, In Gab; Yoo, Sangjun; Ahn, Jae Beom; You, Dalsan; Pak, Jhang Ho; Kim, Sujong; Hwang, Jung Jin; Kim, Choung-Soo

    2017-07-01

    Androgen and androgen receptor (AR) play essential roles in the development and maintenance of prostate cancer. The recently identified AR splice variants (AR-Vs) have been considered as a plausible mechanism for the primary resistance against androgen deprivation therapy (ADT) in castration-resistant prostate cancer (CRPC). Sodium meta-arsenite (NaAsO 2 ; KML001; Kominox), a trivalent arsenical, is an orally bioavailable and water soluble, which is currently in phase I/II clinical trials for the treatment of prostate cancer. It has a potent anti-cancer effect on prostate cancer cells and xenografts. The aim of this study was to examine the effect of NaAsO 2 on AR signaling in LNCaP and 22Rv1 CRPC cells. We used hormone-sensitive LNCaP cells, hormone-insensitive 22Rv1 cells, and CRPC patient-derived primary cells. We analyzed anti-cancer effect of NaAsO 2 using real-time quantitative reverse transcription-PCR, Western blotting, immunofluorescence staining and CellTiter Glo® luminescent assay. Statistical evaluation of the results was performed by one-way ANOVA. NaAsO 2 significantly reduced the translocation of AR and AR-Vs to the nucleus as well as their level in LNCaP and 22Rv1 cells. Besides, the level of the prostate-specific antigen (PSA), downstream target gene of AR, was also decreased. This compound was also an effective modulator of AKT-dependent NF-κB activation which regulates AR. NaAsO 2 significantly inhibited phosphorylation of AKT and expression and nuclear translocation of NF-κB. We then investigated the effect of NaAsO 2 on AR stabilization. NaAsO 2 promoted HSP90 acetylation by down-regulating HDAC6, which reduces the stability of AR in prostate cancer cells. Here, we show that NaAsO 2 disrupts AR signaling at multiple levels by affecting AR expression, stability, and degradation in primary tumor cell cultures from prostate cancer patients as well as CRPC cell lines. These results suggest that NaAsO 2 could be a novel therapeutics for prostate

  16. Evidence for specific TRPM8 expression in human prostate secretory epithelial cells: functional androgen receptor requirement.

    NARCIS (Netherlands)

    Bidaux, G.; Roudbaraki, M.; Merle, C.; Crepin, A.; Delcourt, P.; Slomianny, C.; Thebault, S.C.; Bonnal, J.L.; Benahmed, M.; Cabon, F.; Mauroy, B.; Prevarskaya, N.

    2005-01-01

    TRPM8 (melastatine-related transient receptor potential member 8), a member of the transient receptor potential (TRP) superfamily of cation channels, has been shown to be a calcium-channel protein. TRPM8 mRNA has also been shown to be overexpressed in prostate cancer and is considered to play an

  17. Evaluation of Androgen Receptor Function in Prostate Cancer Prognosis and Therapeutic Stratification

    Science.gov (United States)

    2013-10-01

    expressed relative to GAPDH. Expression results were calculated from the average CT ( threshold cycle) values of triplicates (Figure 5.). A TMPRSS2...useful marker for differentiating indolent from aggressive prostate tumors. Indeed, there is an apparent discordance between AR levels and AR

  18. Ethanolic extracts of herbal supplement Equiguard suppress growth and control gene expression in CWR22Rv1 cells representing the transition of prostate cancer from androgen dependence to hormone refractory status.

    Science.gov (United States)

    Hsieh, Tze-Chen; Wu, Joseph M

    2008-01-01

    Dietary supplements and botanical products are widely used by patients diagnosed with prostate cancer (CaP) as a primary or adjuvant form of treatment for their medical conditions in the United States. Many of the available products are complex mixtures composed of extracts from foreign plants, whose mechanism of action typically is not systematically and rigorously investigated. Laboratory studies employing precisely defined conditions and referenced methodologies are essential not only for standardization and characterization of the products, but are also important requisites for providing scientific evidence and molecular insights in regard to the clinical efficacies some of these products purportedly demonstrate. In previous studies from this laboratory, we serendipitously observed that Equiguard, a dietary supplement formulated with extracts from nine Chinese herbs for preventing decline in renal functions associated with the aging process, contain 70% ethanol-extractable ingredients that displayed potent growth inhibitory activities in androgen-dependent (AD) LNCaP and androgen-independent (AI) DU-145 and PC-3 cells. Moreover, significant reduction in expression of the androgen receptor (AR) and prostate specific antigen (PSA) also occurred in Equiguard-treated LNCaP cells. Although these results offer the possibility that Equiguard confers chemoprevention for CaP, it remains undetermined whether Equiguard functions in CaP cell types that represent the transition of AD to the AI status. Further, details of its mechanism of action have not been fully elucidated. The studies described in this report focusing on CWR22Rv1 cells are intended to fill these gaps. These cells express AR and PSA, yet show weak responsiveness to androgens and largely proliferate in an AI-independent manner - features that mimic AD --> AI in clinically advanced disease. Using the CWR22Rv1 cells, we showed that 70% ethanolic extracts of Equiguard effectively suppressed colony formation

  19. Clinical (non-histological) diagnosis of advanced prostate cancer: Evaluation of treatment outcome after androgen deprivation therapy.

    Science.gov (United States)

    Heyns, Chris F; Basson, Jacque; Van der Merwe, Andre; Zarrabi, Amir D

    2014-08-08

    Introduction. Transrectal biopsy in suspected adenocarcinoma of the prostate (ACP) may cause significant morbidity and even mortality. A strong association between serum prostate-specific antigen (PSA) and tumour burden exists. If biopsy can be avoided in advanced disease, much morbidity and cost may be saved.Objective. To evaluate the reliability of using PSA and clinical features to establish a non-histological diagnosis of ACP.Methods. Androgen deprivation therapy (ADT) was used in 825 (56.2%) of 1 467 men with ACP. The diagnosis of ACP was made histologically in 607 patients (73.6%) and clinically alone in 218 (26.4%), based on a serum PSA level of >60 ng/ml, and/or clinical evidence of a T3 - T4 tumour on digital rectal examination, and/or imaging evidence of metastases. We compared two randomly selected groups treated with bilateral orchidectomy (BO) based on a clinical-only (n=90) v. histological (n=96) diagnosis of ACP.Results. There was no significant difference between the groups with regard to mean follow-up (26.1 v. 26.8 months), documented PSA relapse (70% v. 67.7%), and patients alive at last follow-up (91.1% v. 95.8%). ZAR1 068 200 (US$1 = ZAR8) was saved by treating men with advanced ACP on the basis of a clinical (non-histological) diagnosis only, and a total of ZAR24 321 000 was saved by using BO instead of luteinising hormone-releasing hormone agonists as ADT.Conclusion. A reliable clinical (non-histological) diagnosis of advanced ACP can be made based on serum PSA and clinical features. This avoids the discomfort and potentially serious complications of biopsy and saves cost.

  20. Clamp ablation of the testes compared to bilateral orchiectomy as androgen deprivation therapy for advanced prostate cancer

    Directory of Open Access Journals (Sweden)

    AD Zarrabi

    2011-06-01

    Full Text Available PURPOSE: Burdizzo clamp ablation of the testes (CAT may provide an incisionless, cost-effective form of androgen deprivation therapy (ADT in men with adenocarcinoma of the prostate (ACP who find bilateral orchiectomy (BO unacceptable or can not afford medical ADT. The aim of this study was to compare CAT with BO as primary ADT in men with ACP. MATERIALS AND METHODS: Written, informed consent was obtained from men with locally advanced or metastatic ACP. Patients were prospectively randomized to BO (n = 9 or CAT (n = 10 under local anaesthesia, and were evaluated 3 and 7 days, 6 weeks and 3 months post-procedure. The protocol was approved by the local institutional ethics committee. Statistical analysis was performed using Student's, Mann-Whitney's and Fisher's tests. RESULTS: Mean duration of the procedure was significantly longer for BO than CAT (16.9 vs. 10.9 minutes. Mean pain scores during and after the procedure did not differ significantly. Serum testosterone decreased significantly on days 3 and 7 after CAT, but increased at 6 weeks, and was significantly higher than after BO. Serum luteinizing hormone increased significantly from day 3 after BO and from day 7 after CAT. Serum prostate specific antigen decreased significantly after BO, but not after CAT. Minor complications were more common after BO (89% than CAT (40%. In the 9 men who did not achieve castrate levels of testosterone after CAT, BO was performed. CONCLUSIONS: CAT was quicker to perform and had a lower complication rate, but was not as effective as BO in achieving castrate serum testosterone levels.

  1. Three linked nomograms for predicting biochemical failure in prostate cancer treated with radiotherapy plus androgen deprivation therapy

    International Nuclear Information System (INIS)

    Lopez-Torrecilla, Jose; Boladeras, Anna; Angeles Cabeza, Maria; Zapatero, Almudena; Jove, Josep; Esteban, Luis M.; Henriquez, Ivan; Casana, Manuel; Mengual, Jose Luis; Gonzalez-San Segundo, Carmen; Gomez-Caamano, Antonio; Hervas, Asuncion; Munoz, Julia Luisa; Sanz, Gerardo

    2015-01-01

    Nomograms were established to predict biochemical recurrence (BCR) after radiotherapy (RT) with a low weight of the characteristic variables of RT and androgen deprivation therapy (ADT). Our aim is to provide a new stratified tool for predicting BCR at 4 and 7 years in patients treated using RT with radical intent. A retrospective, nonrandomized analysis was performed on 5044 prostate cancer (PCa) patients with median age 70 years, who received RT - with or without ADT - between November 1992 and May 2007. Median follow-up was 5.5 years. BCR was defined as a rise in serum prostate-specific antigen (PSA) of 2 ng/ml over the post-treatment PSA nadir. Univariate association between predictor variables and BCR was assessed by the log-rank test, and three linked nomograms were created for multivariate prognosis of BCR-free survival. Each nomogram corresponds to a category of the Gleason score - either 6,7, or 8-10 - and all of them were created from a single proportional hazards regression model stratified also by months of ADT (0, 1-6, 7-12, 13-24, 25-36, 36-60). The performance of this model was analyzed by calibration, discrimination, and clinical utility. Initial PSA, clinical stage, and RT dose were significant variables (p < 0.01). The model showed a good calibration. The concordance probability was 0.779, improving those obtained with other nomograms (0.587, 0.571, 0.554) in the database. Survival curves showed best clinical utility in a comparison with National Comprehensive Cancer Network (NCCN) risk groups. For each Gleason score category, the nomogram provides information on the benefit of adding ADT to a specific RT dose. (orig.) [de

  2. GEN GEN: the genomic genetic analysis of androgen-metabolic genes and prostate cancer as a paradigm for the dissection of complex phenotypes.

    Science.gov (United States)

    Reichardt, J K

    1999-07-15

    Prostate cancer will be diagnosed in about 179,300 men in the US in 1999 alone. Some 37,000 individuals die of this disease annually. Prostate cancer is characterized by a substantial racial/ethnic variation in risk: highest in African-American men, lowest in Asian men and intermediate in Caucasian and Latino men. We set out to investigate as our central hypothesis that genetic variants of genes involved in androgen metabolism by themselves and in combination significantly contribute to prostate cancer progression and its racial/ethnic variation. Specifically, we examined the hypothesis that DNA sequence (allelic) variations in the type II (or prostatic) steroid 5alpha-reductase (SRD5A2) gene contribute substantially to the risk and progression of prostate cancer particularly across racial/ethnic lines. The "candidate gene", SRD5A2, was chosen because the reaction product [i.e. dihydrotestosterone (DHT)] of the enzyme encoded by this gene modulates directly cell division in the prostate. DHT binds to the androgen receptor (AR) and the DHT-AR complex leads to the transactivation of a variety of genes which ultimately modulates cell division in the prostate. Epidemiologic evidence suggests that variation in DHT levels play an important role in risk of prostate cancer. Thus, steroid 5alpha-reductase activity encoded by SRD5A2 variant alleles may be important in regulating intraprostatic DHT steady state levels by controlling its biosynthesis. A second candidate gene, the type II 3beta-hydroxysteroid dehydrogenase (HSD3B2) gene, encodes the enzyme that initiates the metabolic inactivation of testosterone (T) to DHT. We have identified allelic variants in this gene as well. Here I review our strategy for identifying candidate genes for prostate cancer, a multifactorial disease. I summarize the significant findings, particularly of allelic variants in the HSD3B2 and SRD5A2 genes and discuss how they by themselves, in combination and through interactions with the

  3. Prostate cancer: assessing the effects of androgen-deprivation therapy using quantitative diffusion-weighted and dynamic contrast-enhanced MRI

    Energy Technology Data Exchange (ETDEWEB)

    Hoetker, Andreas M. [Memorial Sloan-Kettering Cancer Center, Department of Radiology, New York, NY (United States); Universitaetsmedizin Mainz, Department of Diagnostic and Interventional Radiology, Mainz (Germany); Mazaheri, Yousef [Memorial Sloan-Kettering Cancer Center, Department of Medical Physics, New York, NY (United States); Zheng, Junting; Moskowitz, Chaya S. [Memorial Sloan-Kettering Cancer Center, Department of Epidemiology and Biostatistics, New York, NY (United States); Berkowitz, Joshua; Pei, Xin; Zelefsky, Michael J. [Memorial Sloan-Kettering Cancer Center, Department of Radiation Oncology, New York, NY (United States); Lantos, Joshua E.; Hricak, Hedvig; Akin, Oguz [Memorial Sloan-Kettering Cancer Center, Department of Radiology, New York, NY (United States)

    2015-09-15

    To investigate the effects of androgen-deprivation therapy (ADT) on MRI parameters and evaluate their associations with treatment response measures. The study included 30 men with histopathologically confirmed prostate cancer who underwent MRI before and after initiation of ADT. Thirty-four tumours were volumetrically assessed on DW-MRI (n = 32) and DCE-MRI (n = 18), along with regions of interest in benign prostatic tissue, to calculate apparent diffusion coefficient (ADC) and transfer constant (K{sup trans}) values. Changes in MRI parameters and correlations with clinical parameters (change in prostate-specific antigen [PSA], treatment duration, PSA nadir) were assessed. Prostate volume and PSA values decreased significantly with therapy (p < 0.001). ADC values increased significantly in tumours and decreased in benign prostatic tissue (p < 0.05). Relative changes in ADC and absolute post-therapeutic ADC values differed significantly between tumour and benign tissue (p < 0.001). K{sup trans} decreased significantly only in tumours (p < 0.001); relative K{sup trans} changes and post-therapeutic values were not significantly different between tumour and benign tissue. The relative change in tumour ADC correlated significantly with PSA decrease. No changes were associated with treatment duration or PSA nadir. Multi-parametric MRI shows significant measurable changes in tumour and benign prostate caused by ADT and may help in monitoring treatment response. (orig.)

  4. Analysis of Morphogenic Effect of hDAB21P on Prostate Cancer and Its Disease Correlation

    National Research Council Canada - National Science Library

    Hsieh, Jer-Tsong

    2008-01-01

    .... In androgen-independent prostate cancer (AIPCa), RAS activation is often detected while DAB2IP is down regulated due to epigenetic control such as DNA methylation and histone acetylation or methylation...

  5. Knock-out transmembrane prostate androgen-induced protein gene suppressed triple-negative breast cancer cell proliferation

    Directory of Open Access Journals (Sweden)

    Bantari W.K. Wardhani

    2017-11-01

    Full Text Available Background: Triple negative breast cancer (TNBC tends to grow more rapidly and has poorer prognosis compared to others. High expression of transmembrane prostate androgen-induced protein (TMEPAI correlates with poor prognosis in TNBC patients. However, the mechanistic role of TMEPAI in tumorigenic remains unknown. This study aimed to knock-out TMEPAI in TNBC cell line to determine its function further in cells proliferation.Methods: CRISPR-Cas9 has been used previously to knock-out TMEPAI in Hs857T TNBC cell line. Hs587T TNBC parental cell line (wild-type/WT and TMEPAI knock out Hs 586T cell lines were cultured in Dulbecco’s modified eagle medium (DMEM supplemented with 10% fetal bovine serum, 1% penicillin-streptomycin and amphotericin B. Both cell lines were seeded in 24-well plates and counted every two days, then proliferation rates were plotted. Afterwards, total RNA were isolated from the cells and Ki-67, and TGF-β mRNA expression levels as proliferation markers were determined.Results: Cell proliferation rates as displayed in growth curve plots showed that WT-TMEPAI cell line grew more rapidly than KO-TMEPAI. In accordance, mRNA expression levels of  Ki-67 and TGF-β  were significantly decreased KO-TMEPAI as compare to TMEPAI-WT.Conclusion: Knock-out of TMEPAI attenuates cell proliferation in TNBC.

  6. Expanded risk groups help determine which prostate radiotherapy sub-group may benefit from adjuvant androgen deprivation therapy

    Directory of Open Access Journals (Sweden)

    Williams Scott G

    2008-04-01

    Full Text Available Abstract Purpose To assess whether an expanded (five level risk stratification system can be used to identify the sub-group of intermediate risk patients with prostate cancer who benefit from combining androgen deprivation therapy (ADT with external beam radiotherapy (EBRT. Materials and methods Using a previously validated 5-risk group schema, a prospective non-randomized data set of 1423 men treated at the British Columbia Cancer Agency was assessed for the primary end point of biochemical control (bNED with the RTOG-ASTRO "Phoenix" definition (lowest PSA to date + 2 ng/mL, both with and without adjuvant ADT. The median follow-up was 5 years. Results There was no bNED benefit for ADT in the low or low intermediate groups but there was a statistically significant bNED benefit in the high intermediate, high and extreme risk groups. The 5-year bNED rates with and without ADT were 70% and 73% respectively for the low intermediate group (p = non-significant and 72% and 58% respectively for the high intermediate group (p = 0.002. Conclusion There appears to be no advantage to ADT where the Gleason score is 6 or less and PSA is 15 or less. ADT is beneficial in patients treated to standard dose radiation with Gleason 6 disease and a PSA greater than 15 or where the Gleason score is 7 or higher.

  7. Strategies for Imaging Androgen Receptor Signaling Pathway in Prostate Cancer: Implications for Hormonal Manipulation and Radiation Treatment

    Directory of Open Access Journals (Sweden)

    Gravina Giovanni Luca

    2013-01-01

    Full Text Available Prostate cancer (Pca is a heterogeneous disease; its etiology appears to be related to genetic and epigenetic factors. Radiotherapy and hormone manipulation are effective treatments, but many tumors will progress despite these treatments. Molecular imaging provides novel opportunities for image-guided optimization and management of these treatment modalities. Here we reviewed the advances in targeted imaging of key biomarkers of androgen receptor signaling pathways. A computerized search was performed to identify all relevant studies in Medline up to 2013. There are well-known limitations and inaccuracies of current imaging approaches for monitoring biological changes governing tumor progression. The close integration of molecular biology and clinical imaging could ease the development of new molecular imaging agents providing novel tools to monitor a number of biological events that, until a few years ago, were studied by conventional molecular assays. Advances in translational research may represent the next step in improving the oncological outcome of men with Pca who remain at high risk for systemic failure. This aim may be obtained by combining the anatomical properties of conventional imaging modalities with biological information to better predict tumor response to conventional treatments.

  8. Activation of P-TEFb by Androgen Receptor-Regulated Enhancer RNAs in Castration-Resistant Prostate Cancer.

    Science.gov (United States)

    Zhao, Yu; Wang, Liguo; Ren, Shancheng; Wang, Lan; Blackburn, Patrick R; McNulty, Melissa S; Gao, Xu; Qiao, Meng; Vessella, Robert L; Kohli, Manish; Zhang, Jun; Karnes, R Jeffrey; Tindall, Donald J; Kim, Youngsoo; MacLeod, Robert; Ekker, Stephen C; Kang, Tiebang; Sun, Yinghao; Huang, Haojie

    2016-04-19

    The androgen receptor (AR) is required for castration-resistant prostate cancer (CRPC) progression, but the function and disease relevance of AR-bound enhancers remain unclear. Here, we identify a group of AR-regulated enhancer RNAs (e.g., PSA eRNA) that are upregulated in CRPC cells, patient-derived xenografts (PDXs), and patient tissues. PSA eRNA binds to CYCLIN T1, activates P-TEFb, and promotes cis and trans target gene transcription by increasing serine-2 phosphorylation of RNA polymerase II (Pol II-Ser2p). We define an HIV-1 TAR RNA-like (TAR-L) motif in PSA eRNA that is required for CYCLIN T1 binding. Using TALEN-mediated gene editing we further demonstrate that this motif is essential for increased Pol II-Ser2p occupancy levels and CRPC cell growth. We have uncovered a P-TEFb activation mechanism and reveal altered eRNA expression that is related to abnormal AR function and may potentially be a therapeutic target in CRPC. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  9. Activation of P-TEFb by Androgen Receptor-Regulated Enhancer RNAs in Castration-Resistant Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Yu Zhao

    2016-04-01

    Full Text Available The androgen receptor (AR is required for castration-resistant prostate cancer (CRPC progression, but the function and disease relevance of AR-bound enhancers remain unclear. Here, we identify a group of AR-regulated enhancer RNAs (e.g., PSA eRNA that are upregulated in CRPC cells, patient-derived xenografts (PDXs, and patient tissues. PSA eRNA binds to CYCLIN T1, activates P-TEFb, and promotes cis and trans target gene transcription by increasing serine-2 phosphorylation of RNA polymerase II (Pol II-Ser2p. We define an HIV-1 TAR RNA-like (TAR-L motif in PSA eRNA that is required for CYCLIN T1 binding. Using TALEN-mediated gene editing we further demonstrate that this motif is essential for increased Pol II-Ser2p occupancy levels and CRPC cell growth. We have uncovered a P-TEFb activation mechanism and reveal altered eRNA expression that is related to abnormal AR function and may potentially be a therapeutic target in CRPC.

  10. NF-kB2/p52 Activation and Androgen Receptor Signaling in Prostate Cancer

    Science.gov (United States)

    2010-08-01

    of prostate cancer (CaP) than Caucasian American (CA) men and men of other ethnic minority groups. The causes of this ethnic disparity in clinical...suppressive subtrac- tive hybridization (SSH), and custom race-based CaP cDNA microarray on fresh specimens. Quantitative RT-PCR and ethnicity -based tissue...with cofactors. One such factor, a scaffolding protein, PELP-1 (Proline, Glutamic acid, Leucine rich Protein 1), has been shown to interact with AR and

  11. Molecular Targeting of Prostate Cancer During Androgen Ablation: Inhibition of CHES1/FOXN3

    Science.gov (United States)

    2013-05-01

    transcript is analyzed in a single reaction . An alternative approach is to use Western immunoblot analysis to define the expression of the 80-kDa AR protein...by oxidative stress promote treatment resistance in prostate cancer, Endocrine-related cancer 2012, 19:R243-253 60. Dutertre M, Sanchez G, Barbier ...dT)12-18 primer as previously described (23). PCR reactions were performed with custom-synthesized primers (Integrated DNA Technologies, Coralville

  12. Androgen depletion induces senescence in prostate cancer cells through down-regulation of Skp2

    Czech Academy of Sciences Publication Activity Database

    Pernicová, Zuzana; Slabáková, Eva; Kharaishvili, G.; Bouchal, J.; Král, M.; Kunická, Z.; Machala, M.; Kozubík, Alois; Souček, Karel

    2011-01-01

    Roč. 13, č. 6 (2011), s. 526-536 ISSN 1522-8002 R&D Projects: GA ČR(CZ) GA310/07/0961; GA MZd NS9600; GA MZd NS9956 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : prostate cancer * senescence * Skp2 Subject RIV: BO - Biophysics Impact factor: 5.946, year: 2011

  13. Soy Phytochemicals and Tea Bioactive Components Synergistically Inhibit Androgen-Sensitive Human Prostate Tumors in Mice

    OpenAIRE

    Zhou, Jin-Rong; Yu, Lunyin; Zhong, Ying; Blackburn, George L.

    2003-01-01

    Although high doses of single bioactive agents may have potent anticancer effects, the chemopreventive properties of the Asian diet may result from interactions among several components that potentiate the activities of any single constituent. In Asia, where intake of soy products and tea consumption are very high, aggressive prostate cancer is significantly less prevalent in Asian men. The objective of the present study was to identify possible synergistic effects between soy and tea compone...

  14. Probing Androgen Receptor Signaling in Circulating Tumor Cells in Prostate Cancer

    Science.gov (United States)

    2013-07-01

    membrane antigen . Proc Natl Acad Sci U S A 2011 ; 108 : 9578 – 82 . 9. Danila DC , Heller G , Gignac GA , Gonzalez -Espinoza R , Anand...13 : 7053 – 8 . 10. Helo P , Cronin AM , Danila DC , Wenske S , Gonzalez -Espinoza R , Anand A , et al. Circulating prostate tumor...mesenchymal transition. J. Clin. Invest. 119, 1420–1428 (2009). 13. O. Lara , X. Tong, M. Zborowski, J. J. Chalmers, Enrichment of rare cancer cells

  15. Is Androgen Deprivation Therapy Necessary in All Intermediate-Risk Prostate Cancer Patients Treated in the Dose Escalation Era?

    Energy Technology Data Exchange (ETDEWEB)

    Castle, Katherine O., E-mail: kocastle@mdanderson.org [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Hoffman, Karen E.; Levy, Lawrence B.; Lee, Andrew K.; Choi, Seungtaek; Nguyen, Quynh N.; Frank, Steven J.; Pugh, Thomas J.; McGuire, Sean E.; Kuban, Deborah A. [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States)

    2013-03-01

    Purpose: The benefit of adding androgen deprivation therapy (ADT) to dose-escalated radiation therapy (RT) for men with intermediate-risk prostate cancer is unclear; therefore, we assessed the impact of adding ADT to dose-escalated RT on freedom from failure (FFF). Methods: Three groups of men treated with intensity modulated RT or 3-dimensional conformal RT (75.6-78 Gy) from 1993-2008 for prostate cancer were categorized as (1) 326 intermediate-risk patients treated with RT alone, (2) 218 intermediate-risk patients treated with RT and ≤6 months of ADT, and (3) 274 low-risk patients treated with definitive RT. Median follow-up was 58 months. Recursive partitioning analysis based on FFF using Gleason score (GS), T stage, and pretreatment PSA concentration was applied to the intermediate-risk patients treated with RT alone. The Kaplan-Meier method was used to estimate 5-year FFF. Results: Based on recursive partitioning analysis, intermediate-risk patients treated with RT alone were divided into 3 prognostic groups: (1) 188 favorable patients: GS 6, ≤T2b or GS 3+4, ≤T1c; (2) 71 marginal patients: GS 3+4, T2a-b; and (3) 68 unfavorable patients: GS 4+3 or T2c disease. Hazard ratios (HR) for recurrence in each group were 1.0, 2.1, and 4.6, respectively. When intermediate-risk patients treated with RT alone were compared to intermediate-risk patients treated with RT and ADT, the greatest benefit from ADT was seen for the unfavorable intermediate-risk patients (FFF, 74% vs 94%, respectively; P=.005). Favorable intermediate-risk patients had no significant benefit from the addition of ADT to RT (FFF, 94% vs 95%, respectively; P=.85), and FFF for favorable intermediate-risk patients treated with RT alone approached that of low-risk patients treated with RT alone (98%). Conclusions: Patients with favorable intermediate-risk prostate cancer did not benefit from the addition of ADT to dose-escalated RT, and their FFF was nearly as good as patients with low-risk disease

  16. Neuroendocrine prostate cancer (NEPCa) increased the neighboring PCa chemo-resistance via altering the PTHrP/p38/Hsp27/androgen receptor (AR)/p21 signals

    Science.gov (United States)

    Cui, Yun; Sun, Yin; Hu, Shuai; Luo, Jie; Li, Lei; Li, Xin; Yeh, Shuyuan; Jin, Jie; Chang, Chawnshang

    2016-01-01

    Prostatic neuroendocrine cells (NE) are an integral part of prostate cancer (PCa) that are associated with PCa progression. As the current androgen-deprivation therapy (ADT) with anti-androgens may promote the neuroendocrine PCa (NEPCa) development, and few therapies can effectively suppress NEPCa, understanding the impact of NEPCa on PCa progression may help us to develop better therapies to battle PCa. Here we found NEPCa cells could increase the docetaxel-resistance of their neighboring PCa cells. Mechanism dissection revealed that through secretion of PTHrP, NEPCa cells could alter the p38/MAPK/Hsp27 signals in their neighboring PCa cells that resulted in increased androgen receptor (AR) activity via promoting AR nuclear translocation. The consequences of increased AR function might then increase docetaxel-resistance via increasing p21 expression. In vivo xenograft mice experiments also confirmed NEPCa could increase the docetaxel-resistance of neighboring PCa, and targeting this newly identified PTHrP/p38/Hsp27/AR/p21 signaling pathway with either p38 inhibitor (SB203580) or sh-PTHrP may result in improving/restoring the docetaxel sensitivity to better suppress PCa. PMID:27375022

  17. Determination of Six Transmembrane Protein of Prostate 2 Gene Expression and Intracellular Localization in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Bora İrer

    2017-12-01

    Full Text Available Objective: In this study, we aimed to determine the relationship between the RNA and protein expression profile of six transmembrane protein of prostate 2 (STAMP2 gene and androgen and the intracellular localization of STAMP2. Materials and Methods: RNA and protein were obtained from androgen treated lymph node carcinoma of the prostate (LNCaP cells, untreated LNCaP cells, DU145 cells with no androgen receptor, and STAMP2 transfected COS-7 cells. The expression profile of STAMP2 gene and the effect of androgenes on the expression was shown in RNA and protein levels by using Northern and Western blotting methods. In addition, intracellular localization of the naturally synthesized STAMP2 protein and the transfected STAMP2 protein in COS-7 cells after androgen administration in both LNCaP cells was determined by immunofluorescence microscopy. Results: We found that the RNA and protein expression of STAMP2 gene in LNCaP cells are regulated by androgenes, the power of expression is increased with the duration of androgen treatment and there is no STAMP2 expression in DU145 cells which has no androgen receptor. As a result of the immunofluorescence microscopy study we observed that STAMP2 protein was localized at golgi complex and cell membrane. Conclusion: In conclusion, we have demonstrated that STAMP2 may play an important role in the pathogenesis of the prostate cancer and in the androgen-dependent androgen-independent staging of prostate cancer. In addition, STAMP2 protein, which is localized in the intracellular golgi complex and cell membrane, may be a new target molecule for prostate cancer diagnosis and treatment.

  18. Comparison of the pharmacological effects of a novel selective androgen receptor modulator, the 5alpha-reductase inhibitor finasteride, and the antiandrogen hydroxyflutamide in intact rats: new approach for benign prostate hyperplasia.

    Science.gov (United States)

    Gao, Wenqing; Kearbey, Jeffrey D; Nair, Vipin A; Chung, Kiwon; Parlow, A F; Miller, Duane D; Dalton, James T

    2004-12-01

    Tissue-selective androgen receptor modulators (SARMs) demonstrate tissue selectivity in both castrated and intact male rats, behaving as partial agonists in androgenic tissues (i.e. prostate and seminal vesicle), but full agonists in anabolic tissues (i.e. levator ani muscle). The partial agonist activity of SARMs (compounds S-1 and S-4) in the prostate of intact rats suggested that SARM could be used for androgen suppression in the treatment of benign prostate hyperplasia (BPH). This study was designed to explore the mechanisms of action of SARM and to characterize the tissue selectivity of S-1 in intact male rats compared with that of hydroxyflutamide (antiandrogen) and finasteride (5alpha-reductase inhibitor), two major drugs used for androgen suppression treatment of BPH. In intact male rats, S-1 (5, 10, and 25 mg/kg) selectively decreased the prostate weight with similar efficacy to finasteride (5 mg/kg), without affecting the levator ani muscle or increasing the plasma levels of testosterone, LH, and FSH. Hydroxyflutamide (0.5, 1, 5, 10, and 25 mg/kg), however, decreased both the prostate and levator ani muscle weights without any selectivity and increased plasma hormone levels in a dose-dependent manner. Furthermore, S-1 and S-4 showed very weak inhibitory effects toward transiently expressed type I and II human 5alpha-reductase (Ki, >20 microm) during in vitro assays. Therefore, although S-1 and finasteride showed very similar suppressive effects in the prostate of intact male rats, they decreased prostate size via different mechanisms of action. S-1 simply worked as androgen receptor partial agonist, whereas finasteride inhibited prostatic 5alpha-reductase. These studies indicate that SARMs may demonstrate clinical utility as single agent or combination therapy for BPH.

  19. Comparison of the Pharmacological Effects of a Novel Selective Androgen Receptor Modulator, the 5α-Reductase Inhibitor Finasteride, and the Antiandrogen Hydroxyflutamide in Intact Rats: New Approach for Benign Prostate Hyperplasia

    Science.gov (United States)

    Gao, Wenqing; Kearbey, Jeffrey D.; Nair, Vipin A.; Chung, Kiwon; Parlow, A. F.; Miller, Duane D.; Dalton, James T.

    2007-01-01

    Tissue-selective androgen receptor modulators (SARMs) demonstrate tissue selectivity in both castrated and intact male rats, behaving as partial agonists in androgenic tissues (i.e. prostate and seminal vesicle), but full agonists in anabolic tissues (i.e. levator ani muscle). The partial agonist activity of SARMs (compounds S-1 and S-4) in the prostate of intact rats suggested that SARM could be used for androgen suppression in the treatment of benign prostate hyperplasia (BPH). This study was designed to explore the mechanisms of action of SARM and to characterize the tissue selectivity of S-1 in intact male rats compared with that of hydroxyflutamide (antiandrogen) and finasteride (5α-reductase inhibitor), two major drugs used for androgen suppression treatment of BPH. In intact male rats, S-1 (5, 10, and 25 mg/kg) selectively decreased the prostate weight with similar efficacy to finasteride (5 mg/kg), without affecting the levator ani muscle or increasing the plasma levels of testosterone, LH, and FSH. Hydroxyflutamide (0.5, 1, 5, 10, and 25 mg/kg), however, decreased both the prostate and levator ani muscle weights without any selectivity and increased plasma hormone levels in a dose-dependent manner. Furthermore, S-1 and S-4 showed very weak inhibitory effects toward transiently expressed type I and II human 5α-reductase (Ki, >20 µM) during in vitro assays. Therefore, although S-1 and finasteride showed very similar suppressive effects in the prostate of intact male rats, they decreased prostate size via different mechanisms of action. S-1 simply worked as androgen receptor partial agonist, whereas finasteride inhibited prostatic 5α-reductase. These studies indicate that SARMs may demonstrate clinical utility as single agent or combination therapy for BPH. PMID:15308613

  20. Long-term effects of developmental exposure to di-n-butyl-phthalate (DBP) on rat prostate: Proliferative and inflammatory disorders and a possible role of androgens

    International Nuclear Information System (INIS)

    Scarano, Wellerson Rodrigo; Toledo, Fabiola Choqueta de; Guerra, Marina Trevizan; Campos, Silvana Gisele Pegorin de; Junior, Luis Antonio Justulin; Felisbino, Sergio Luis; Anselmo-Franci, Janete A.; Taboga, Sebastiao Roberto; Kempinas, Wilma De Grava

    2009-01-01

    In the present study we evaluated the toxic effects on the male adult rat prostate of DBP exposure during fetal and lactational periods, because although many studies have addressed the influence of phthalates on the male reproductive system, only a few have discussed their possible effects on prostate development. Pregnant females were distributed into two experimental groups: Control (C) and Treated (T). The females of the T group received DBP (100 mg/kg, by gavage) from gestation day 12 to postnatal day 21, while C rats received the vehicle (corn oil). In adulthood (90 days old), the animals were euthanized. The serum and testicular testosterone levels were measured. Ventral prostate was removed and weighed. Distal segment fragments of the ventral prostate were fixed and processed for histochemistry and immunohistochemistry to detect androgen receptor (AR) and Ki67 antigens. Protein extraction from ventral prostate fragments was performed for AR immunoblotting and Gelatin zymography for MMP-2 and MMP-9 (MMP, metalloproteinase). Stereological and histopathological analyses were also performed. Serum and testicular testosterone levels and prostate weight were comparable between groups. In the T group the relative proportions (%) of epithelial (C = 32.86; T = 42.04*) and stromal (C = 21.61; T = 27.88*) compartments were increased, while the luminal compartment was decreased (C = 45.54; T = 30.08*), *p < 0.05. In T, disseminated inflammatory infiltrate in the stroma, associated or not with epithelial dysplasia and PIN (Prostatic Intraepithelial Neoplasia), was observed. Increases in AR expression, proliferation index and metalloproteinase 9 (MMP-9) activity were noted in T animals. In some T animals, collagen fibrils accumulated adjacent to the epithelium. As far as we are aware, this is the first report in the literature showing that phthalates could play a role in proliferative and inflammatory disorders of the rat prostate.

  1. Abnormal P-53 suppressor gene expression predicts for a poorer outcome in patients with locally advanced adenocarcinoma of the prostate treated by external beam radiation therapy with or without pre-radiation androgen ablation: results based on RTOG study 86-10

    International Nuclear Information System (INIS)

    Lawton, Colleen A.; Grignon, David; Caplan, Richard; Sarkar, Fazlul; Forman, Jeffrey; Mesic, John; Fu, Karen K.; Abrams, Ross

    1995-01-01

    Purpose/Objective: The purpose of this study is to establish the effect of the abnormal expression of the P-53 suppressor gene on the results of locally advanced adenocarcinoma of the prostate treated with radiation therapy with or without pre-radiation therapy androgen ablation. Materials and Methods: Patients evaluated were part of a RTOG phase III multi-institutional trial. This trial assessed the value of pre-radiation therapy androgen ablation on patients with locally advanced disease (bulky stage B and stage C). Of the 471 patients registered, pre-treatment pathological material was available for 129 patients. P-53 status was determined immunohistochemically utilizing a commercially available antibody (D07). Clinical endpoints evaluated were overall survival and development of metastases. Results: Twenty-three of the 129 patients had abnormal expression of the P-53 suppressor gene. Presence of this abnormal expression significantly correlated with lower overall survival (p=0.03) and the development of distant metastases (p=0.03). Abnormal expression of the P-53 gene was an independent prognostic indicator when evaluated against clinical stage and Gleason score. Conclusion: This data from patients entered on a phase III multi-institutional, randomized clinical trial shows that abnormal P-53 suppressor gene expression as determined immunohistochemically is an independent predictor of poorer survival and the development of distant metastases in patients with locally advanced adenocarcinoma of the prostate treated with radiation therapy with or without pre-radiation therapy androgen ablation

  2. Total Androgen Blockade Versus a Luteinizing Hormone-Releasing Hormone Agonist Alone in Men With High-Risk Prostate Cancer Treated With Radiotherapy

    International Nuclear Information System (INIS)

    Nanda, Akash; Chen, M.-H.; Moran, Brian J.; Braccioforte, Michelle H.; Dosoretz, Daniel; Salenius, Sharon; Katin, Michael; Ross, Rudi; D'Amico, Anthony V.

    2010-01-01

    Purpose: To assess whether short-course total androgen blockade vs. a luteinizing hormone-releasing hormone (LHRH) agonist alone affects the risk of prostate cancer-specific mortality (PCSM) in men with localized but high-risk disease treated with radiotherapy. Methods and Materials: The study cohort comprised 628 men with T1-T4, N0, M0 prostate cancer with high-risk disease (prostate-specific antigen level >20 ng/mL, Gleason score ≥8, or clinical category ≥T3) treated with 45 Gy of external beam radiotherapy followed by a brachytherapy boost in addition to receiving a median of 4.3 (interquartile range [IQR], 3.6-6.4) months of hormonal blockade with an LHRH agonist plus an antiandrogen or monotherapy with an LHRH agonist. Fine and Gray's multivariable regression analysis was used to determine whether combination androgen suppression therapy (AST) vs. monotherapy affected the risk of PCSM, adjusting for treatment year, duration of AST, age, and known prognostic factors. Results: After a median follow-up of 4.9 (IQR, 3.5-6.5) years, men receiving combination AST had a lower risk of PCSM than those treated with monotherapy (adjusted hazard ratio [AHR], 0.18; 95% confidence interval [CI], 0.04-0.90; p = 0.04). An increasing prostate-specific antigen level (AHR, 2.70; 95% CI, 1.64-4.45; p < 0.001) and clinical category T3/4 disease (AHR, 29.6; 95% CI, 2.88-303.5; p = 0.004) were also associated with an increased risk of PCSM. Conclusions: In men with localized but high-risk prostate cancer treated with external beam radiotherapy and brachytherapy, short-course AST with an LHRH agonist plus an antiandrogen is associated with a decreased risk of PCSM when compared with monotherapy with an LHRH agonist.

  3. Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer

    OpenAIRE

    Asim, Mohammad; Tarish, Firas; Zecchini, Heather I.; Sanjiv, Kumar; Gelali, Eleni; Massie, Charles E.; Baridi, Ajoeb; Warren, Anne Y.; Zhao, Wanfeng; Ogris, Christoph; McDuffus, Leigh-Anne; Mascalchi, Patrice; Shaw, Greg; Dev, Harveer; Wadhwa, Karan

    2017-01-01

    This study was supported by the National Cancer Research Institute (National Institute of Health Research (NIHR) Collaborative Study: ‘Prostate Cancer: Mechanisms of Progression and Treatment (PROMPT)” (grant G0500966/75466). This work was funded by a Cancer Research UK program grant (D.N.), the Swedish Research Council (T.H.), AFA insurance (T.H.), Swedish Cancer Society (T.H.), the Swedish Pain Relief Foundation (T.H.), the Torsten and Ragnar Söderberg Foundation (T.H.), AstraZeneca (T.H.) ...

  4. Molecular Targeting of Prostate Cancer During Androgen Ablation: Inhibition of CHES1/FOXN3

    Science.gov (United States)

    2010-05-10

    prostate cancer cells. N. Xiang, J. K. Yang, J. M. Webb, C. B. Wee, D. L. Boucher, S. Y . Liu, C. A. Baron, R. W. de Vere White, J. P. Gregg, H. J. Kung... cancer agents mitomycin C and doxorubicin were shown to increase apoptosis susceptibility via a p53- dependent induction of the CD95 /APO-1/Fas death... cancer . Oncogene, 20: 7342-7351, 2001. 14. Huang, H., Cheville, J. C., Pan, Y ., Roche, P. C., Schmidt, L. J., and Tindall, D. J. PTEN induces

  5. PCA3 noncoding RNA is involved in the control of prostate-cancer cell survival and modulates androgen receptor signaling

    International Nuclear Information System (INIS)

    Ferreira, Luciana Bueno; Gimba, Etel Rodrigues Pereira; Palumbo, Antonio; Mello, Kivvi Duarte de; Sternberg, Cinthya; Caetano, Mauricio S; Oliveira, Felipe Leite de; Neves, Adriana Freitas; Nasciutti, Luiz Eurico; Goulart, Luiz Ricardo

    2012-01-01

    PCA3 is a non-coding RNA (ncRNA) that is highly expressed in prostate cancer (PCa) cells, but its functional role is unknown. To investigate its putative function in PCa biology, we used gene expression knockdown by small interference RNA, and also analyzed its involvement in androgen receptor (AR) signaling. LNCaP and PC3 cells were used as in vitro models for these functional assays, and three different siRNA sequences were specifically designed to target PCA3 exon 4. Transfected cells were analyzed by real-time qRT-PCR and cell growth, viability, and apoptosis assays. Associations between PCA3 and the androgen-receptor (AR) signaling pathway were investigated by treating LNCaP cells with 100 nM dihydrotestosterone (DHT) and with its antagonist (flutamide), and analyzing the expression of some AR-modulated genes (TMPRSS2, NDRG1, GREB1, PSA, AR, FGF8, CdK1, CdK2 and PMEPA1). PCA3 expression levels were investigated in different cell compartments by using differential centrifugation and qRT-PCR. LNCaP siPCA3-transfected cells significantly inhibited cell growth and viability, and increased the proportion of cells in the sub G0/G1 phase of the cell cycle and the percentage of pyknotic nuclei, compared to those transfected with scramble siRNA (siSCr)-transfected cells. DHT-treated LNCaP cells induced a significant upregulation of PCA3 expression, which was reversed by flutamide. In siPCA3/LNCaP-transfected cells, the expression of AR target genes was downregulated compared to siSCr-transfected cells. The siPCA3 transfection also counteracted DHT stimulatory effects on the AR signaling cascade, significantly downregulating expression of the AR target gene. Analysis of PCA3 expression in different cell compartments provided evidence that the main functional roles of PCA3 occur in the nuclei and microsomal cell fractions. Our findings suggest that the ncRNA PCA3 is involved in the control of PCa cell survival, in part through modulating AR signaling, which may raise new

  6. Multi-institutional Evaluation of Elective Nodal Irradiation and/or Androgen Deprivation Therapy with Postprostatectomy Salvage Radiotherapy for Prostate Cancer.

    Science.gov (United States)

    Ramey, Stephen J; Agrawal, Shree; Abramowitz, Matthew C; Moghanaki, Drew; Pisansky, Thomas M; Efstathiou, Jason A; Michalski, Jeff M; Spratt, Daniel E; Hearn, Jason W D; Koontz, Bridget F; Liauw, Stanley L; Pollack, Alan; Anscher, Mitchell S; Den, Robert B; Stephans, Kevin L; Zietman, Anthony L; Lee, W Robert; Stephenson, Andrew J; Tendulkar, Rahul D

    2017-11-09

    Outcomes with postprostatectomy salvage radiation therapy (SRT) are not ideal. Little evidence exists regarding potential benefits of adding whole pelvic radiation therapy (WPRT) alone or in combination with androgen deprivation therapy (ADT). To explore whether WPRT and/or ADT added to prostate bed radiation therapy (PBRT) improves freedom from biochemical failure (FFBF) or distant metastases (DM). A database was compiled from 10 academic institutions of patients with postprostatectomy prostate-specific antigen (PSA) >0.01 ng/ml; pT1-4, Nx/0, cM0; and Gleason score (GS) ≥7 treated between 1987 and 2013. Median follow-up was 51 mo. WPRT and/or ADT in addition to PBRT. FFBF and DM were calculated using cumulative incidence estimation. Multivariable analysis (MVA) utilized cumulative incidence regression. Median pre-SRT PSA was 0.5 ng/ml for 1861 patients. Median follow-up for patients not experiencing biochemical failure (BF) was 55 mo. MVA showed increased BF for PBRT versus WPRT (hazard ratio [HR] 1.82, pevaluated patients with prostate cancer treated with radiation after surgery to remove the prostate. Both radiation to the pelvic lymph nodes and suppression of testosterone lowered the chance of increasing prostate-specific antigen (a marker for cancer returning). Copyright © 2017 European Association of Urology. All rights reserved.

  7. Maximum androgen blockade in advanced prostate cancer: a meta-analysis of published randomized controlled trials using nonsteroidal antiandrogens.

    Science.gov (United States)

    Caubet, J F; Tosteson, T D; Dong, E W; Naylon, E M; Whiting, G W; Ernstoff, M S; Ross, S D

    1997-01-01

    To assess the survival benefit of maximum androgen blockade (MAB) using nonsteroidal antiandrogens (NSAAs) through meta-analysis of published randomized controlled trials (RCTs). All RCTs comparing treatment with NSAA plus either luteinizing hormone-releasing hormone (LHRH) or orchiectomy versus treatment with LHRH or orchiectomy alone were included if the necessary statistical summaries were present in the publication. Estimates and standard errors of log hazard ratio for overall survival and progression-free survival were derived from published studies using two methods: (1) reconstructing an annual life table from graphical presentations of survival distributions and fitting discrete proportional hazard models, and (2) reconstructing the log hazard ratio from reported P values and numbers of deaths. An alternative set of log hazard ratios was derived from figures presented in a summary report by the Prostate Cancer Trialists' Collaborative Group (PCTCG). Comparative meta-analyses were performed using the random effects approach of DerSimonian and Laird. Additionally, published studies were used in a random-effects-based meta-analysis of objective tumor response. Nine studies provided enough information to perform a meta-analysis for survival using one of the two methods. Estimates of relative risks (RR) comparing treatment with NSAA plus either LHRH or orchiectomy versus treatment with LHRH or orchiectomy alone with respect to overall survival were 0.78 (95% confidence intervals [CIs] 0.67 to 0.90) using method 1, and 0.84 (95% CI 0.76 to 0.93) using method 2. Sensitivity analyses based on PCTCG data showed that a favorable survival result for MAB was associated with NSAAs but not with steroidal antiandrogens and depended on randomization blinding and overall trial quality. Additionally, random-effects-based meta-analysis of published studies showed a significant increase in time-to-progression (RR = 0.74; 95% CI 0.63 to 0.86) and an increase in objective tumor

  8. Biochemical failure and the temporal kinetics of prostate-specific antigen after radiation therapy with androgen deprivation

    International Nuclear Information System (INIS)

    Buyyounouski, Mark K.; Hanlon, Alexandra L.; Horwitz, Eric M.; Uzzo, Robert G.; Pollack, Alan

    2005-01-01

    Purpose: The accuracy of the American Society of Therapeutic Radiation Oncology consensus definition of biochemical failure (BF) after radiation therapy (RT) and androgen deprivation (AD) has been questioned, because posttreatment prostate-specific antigen (PSA) levels typically rise after release from AD, and misclassification of BF may be made. The temporal kinetics of posttreatment PSA levels was examined to define the error in the classification of BF. Methods and Materials: Between December 1, 1991 and April 30, 1998, 688 men with T1c-T3 NX/0 M0 prostate cancer received three-dimensional conformal RT alone (n = 586) or in combination with either short-term (STAD: 3 to 12 months, n = 82) or long-term (LTAD: 12 to 36 months, n = 20) AD. Follow-up, calculated from the end of all treatment, was ≥48 months. The mean posttreatment PSA was calculated in 3-month intervals. Results: The median posttreatment clinical follow-up period was 76 months (range, 48-152 months). The posttreatment PSA values from the end of all treatment for the RT+STAD-BF group showed an initial period of rise followed by a period of decline at 30 months and then a continued rise again. The decline in the mean posttreatment PSA is explained in part by stabilization in PSA level after 3 consecutive rises. Nonbiochemical failures (NBF) after RT+STAD had a relatively constant mean PSA over time of approximately 0.5 ng/mL. Unlike the RT+STAD-NBF profile, the RT+LTAD-NBF profile rose continuously and steadily to a level approaching 1 ng/mL. The RT+LTAD-BF profile rose continuously but at a slower rate over time. Nine RT+STAD-NBF patients (22%) and 2 RT+LTAD-BF (29%) patients experienced 3 consecutive rises followed by a subsequent decline and stabilization of PSA compared to 10 RT-BF patients (5%). Redistributing these misclassified patients to their respective NBF groups changed the mean posttreatment PSA profiles as follows: The RT+LTAD-BF profile rose constantly and steadily with a doubling

  9. Survival benefit of early androgen receptor inhibitor therapy in locally advanced prostate cancer

    DEFF Research Database (Denmark)

    Thomsen, Frederik B; Brasso, Klaus; Christensen, Ib J

    2015-01-01

    disease (hazard ratios (HR)=0.77 (95% confidence interval (CI): 0.63-0.94, p=0.01), regardless of baseline prostate-specific antigen (PSA), with a survival benefit which was apparent throughout the study period. In contrast, survival favoured randomisation to the placebo arm in patients with localised...... disease (HR=1.19 (95% CI: 1.00-1.43), p=0.056). However, a survival gain from bicalutamide therapy was present in patients with localised disease and a baseline PSA greater than 28ng/mL at randomisation. In multivariate Cox proportional hazard model, only including patients managed on watchful waiting...... as their standard of care (n=991) OS depended on age, World Health Organisation (WHO) grade, baseline PSA, clinical stage and randomised treatment. INTERPRETATION: Throughout the 14.6year follow-up period the addition of early bicalutamide to standard of care resulted in a significant OS benefit in patients...

  10. Decision analytic cost-effectiveness model to compare prostate cryotherapy to androgen deprivation therapy for treatment of radiation recurrent prostate cancer

    Science.gov (United States)

    Boyd, Kathleen A; Jones, Rob J; Paul, Jim; Birrell, Fiona; Briggs, Andrew H; Leung, Hing Y

    2015-01-01

    Objective To determine the cost-effectiveness of salvage cryotherapy (SC) in men with radiation recurrent prostate cancer (RRPC). Design Cost-utility analysis using decision analytic modelling by a Markov model. Setting and methods Compared SC and androgen deprivation therapy (ADT) in a cohort of patients with RRPC (biopsy proven local recurrence, no evidence of metastatic disease). A literature review captured published data to inform the decision model, and resource use data were from the Scottish Prostate Cryotherapy Service. The model was run in monthly cycles for RRPC men, mean age of 70 years. The model was run over the patient lifetime, to assess changes in patient health states and the associated quality of life, survival and cost impacts. Results are reported in terms of the discounted incremental costs and discounted incremental quality-adjusted life years (QALYs) gained between the 2 alternative interventions. Probabilistic sensitivity analysis used a 10 000 iteration Monte Carlo simulation. Results SC has a high upfront treatment cost, but delays the ongoing monthly cost of ADT. SC is the dominant strategy over the patient lifetime; it is more effective with an incremental 0.56 QALY gain (95% CI 0.28 to 0.87), and less costly with a reduced lifetime cost of £29 719 (€37 619) (95% CI −51 985 to −9243). For a ceiling ratio of £30 000, SC has a 100% probability to be cost-effective. The cost neutral point was at 3.5 years, when the upfront cost of SC (plus any subsequent cumulative cost of side effects and ADT) equates the cumulative cost in the ADT arm. Limitations of our model may arise from its insensitivity to parameter or structural uncertainty. Conclusions The platform for SC versus ADT cost-effective analysis can be employed to evaluate other treatment modalities or strategies in RRPC. SC is the dominant strategy, costing less over a patient's lifetime with improvements in QALYs. Trial registration number This economic analysis

  11. Does primary androgen-deprivation therapy delay the receipt of secondary cancer therapy for localized prostate cancer?

    Science.gov (United States)

    Lu-Yao, Grace L; Albertsen, Peter C; Li, Hui; Moore, Dirk F; Shih, Weichung; Lin, Yong; DiPaola, Robert S; Yao, Siu-Long

    2012-12-01

    Despite evidence that shows no survival advantage, many older patients receive primary androgen-deprivation therapy (PADT) shortly after the diagnosis of localized prostate cancer (PCa). This study evaluates whether the early use of PADT affects the subsequent receipt of additional palliative cancer treatments such as chemotherapy, palliative radiation therapy, or intervention for spinal cord compression or bladder outlet obstruction. This longitudinal population-based cohort study consists of Medicare patients aged ≥ 66 yr diagnosed with localized PCa from 1992 to 2006 in areas covered by the Surveillance Epidemiology and End Results (SEER) program. SEER-Medicare linked data through 2009 were used to identify the use of PADT and palliative cancer therapy. Instrumental variable analysis methods were used to minimize confounding effects. Confidence intervals were derived from the bootstrap estimates. This study includes 29 775 men who did not receive local therapy for T1-T2 PCa within the first year of cancer diagnosis. Among low-risk patients (Gleason score 2-7 in 1992-2002 and Gleason score 2-6 in 2003-2006) with a median age of 78 yr and a median follow-up of 10.3 yr, PADT was associated with a 25% higher use of chemotherapy (hazard ratio [HR]: 1.25; 95% confidence interval [CI], 1.08-1.44) and a borderline higher use of any palliative cancer treatment (HR: 1.07; 95% CI, 0.97-1.19) within 10 yr of diagnosis in regions with high PADT use compared with regions with low PADT use. Because this study was limited to men >65 yr, the results may not be applicable to younger patients. Early treatment of low-risk, localized PCa with PADT does not delay the receipt of subsequent palliative therapies and is associated with an increased use of chemotherapy. Copyright © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.

  12. Radical Prostatectomy Versus Radiation and Androgen Deprivation Therapy for Clinically Localized Prostate Cancer: How Good Is the Evidence?

    Energy Technology Data Exchange (ETDEWEB)

    Roach, Mack, E-mail: mroach@radonc.ucsf.edu [Department of Radiation Oncology, University of California San Francisco, San Francisco, California (United States); Ceron Lizarraga, Tania L. [Department of Radiation Oncology, University of California San Francisco, San Francisco, California (United States); Lazar, Ann A. [Department of Radiation Oncology, University of California San Francisco, San Francisco, California (United States); Division of Oral Epidemiology and Dental Public Health, Division of Biostatistics, University of California San Francisco, San Francisco, California (United States)

    2015-12-01

    Purpose: The optimal treatment of clinically localized prostate cancer is controversial. Most studies focus on biochemical (PSA) failure when comparing radical prostatectomy (RP) with radiation therapy (RT), but this endpoint has not been validated as predictive of overall survival (OS) or cause-specific survival (CSS). We analyzed the available literature to determine whether reliable conclusions could be made concerning the effectiveness of RP compared with RT with or without androgen deprivation therapy (ADT), assuming current treatment standards. Methods: Articles published between February 29, 2004, and March 1, 2015, that compared OS and CSS after RP or RT with or without ADT were included. Because the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) system emphasis is on randomized controlled clinical trials, a reliability score (RS) was explored to further understand the issues associated with the study quality of observational studies, including appropriateness of treatment, source of data, clinical characteristics, and comorbidity. Lower RS values indicated lower reliability. Results: Fourteen studies were identified, and 13 were completely evaluable. Thirteen of the 14 studies (93%) were observational studies with low-quality evidence. The median RS was 12 (range, 5-18); the median difference in 10-year OS and CSS favored RP over RT: 10% and 4%, respectively. In studies with a RS ≤12 (average RS 9) the 10-year OS and CSS median differences were 17% and 6%, respectively. For studies with a RS >12 (average RS 15.5), the 10-year OS and CSS median differences were 5.5% and 1%, respectively. Thus, we observed an association between low RS and a higher percentage difference in OS and CSS. Conclusions: Reliable evidence that RP provides a superior CSS to RT with ADT is lacking. The most reliable studies suggest that the differences in 10-year CSS between RP and RT are small, possibly <1%.

  13. Strength training induces muscle hypertrophy and functional gains in black prostate cancer patients despite androgen deprivation therapy.

    Science.gov (United States)

    Hanson, Erik D; Sheaff, Andrew K; Sood, Suchi; Ma, Lei; Francis, Jack D; Goldberg, Andrew P; Hurley, Ben F

    2013-04-01

    Androgen deprivation therapy (ADT) for prostate cancer (PCa) is associated with weakness, fatigue, sarcopenia, and reduced quality of life (QoL). Black men have a higher incidence and mortality from PCa than Caucasians. We hypothesized that despite ADT, strength training (ST) would increase muscle power and size, thereby improving body composition, physical function, fatigue levels, and QoL in older black men with PCa. Muscle mass, power, strength, endurance, physical function, fatigue perception, and QoL were measured in 17 black men with PCa on ADT before and after 12 weeks of ST. Within-group differences were determined using t tests and regression models. ST significantly increased total body muscle mass (2.7%), thigh muscle volume (6.4%), power (17%), and strength (28%). There were significant increases in functional performance (20%), muscle endurance (110%), and QoL scores (7%) and decreases in fatigue perception (38%). Improved muscle function was associated with higher functional performance (R (2) = 0.54) and lower fatigue perception (R (2) = 0.37), and both were associated with improved QoL (R (2) = 0.45), whereas fatigue perception tended to be associated with muscle endurance (R (2) = 0.37). ST elicits muscle hypertrophy even in the absence of testosterone and is effective in counteracting the adverse functional consequences of ADT in older black men with PCa. These improvements are associated with reduced fatigue perception, enhanced physical performance, and improved QoL. Thus, ST may be a safe and well-tolerated therapy to prevent the loss of muscle mass, strength, and power commonly observed during ADT.

  14. A quality assurance audit: phase iii trial of maximal androgen deprivation in prostate cancer (TROG 96.01)

    International Nuclear Information System (INIS)

    Steigler, A.; Kovacev, O.; Denham, J.; Lamb, D.; North, J.

    2000-01-01

    In 1997 the Trans-Tasman Radiation Oncology Group (TROG) performed a quality assurance (QA) audit of its phase III randomized clinical trial investigating the effectiveness of different durations of maximal androgen deprivation prior to and during definitive radiation therapy for locally advanced carcinoma of the prostate (TROG 96.01). The audit reviewed a total of 60 cases from 15 centres across Australia and New Zealand. In addition to verification of technical adherence to the protocol, the audit also incorporated a survey of centre planning techniques and a QA time/cost analysis. The present report builds on TROG's first technical audit conducted in 1996 for the phase III accelerated head and neck trial (TROG 91.01) and highlights the significant progress TROG has made in the interim period. The audit provides a strong validation of the results of the 96.01 trial, as well as valuable budgeting and treatment planning information for future trials. Overall improvements were detected in data quality and quantity, and in protocol compliance, with a reduction in the rate of unacceptable protocol violations from 10 to 4%. Audit design, staff education and increased data management resources were identified as the main contributing factors to these improvements. In addition, a budget estimate of $100 per patient has been proposed for conducting similar technical audits. The next major QA project to be undertaken by TROG during the period 1998-1999 is an intercentre dosimetry study. Trial funding and staff education have been targeted as the key major issues essential to the continued success and expansion of TROG's QA programme. Copyright (1999) Blackwell Science Pty Ltd

  15. Targeting Ligand Dependent and Ligand Independent Androgen Receptor Signaling in Prostate Cancer

    Science.gov (United States)

    2014-10-01

    responsible for histone H4 lysine 16 acetylation) and NSL (responsible for histone H4 lysine 5 and 6 acetylation) protein complexes, both of which contain...modification and facilitates the recruitment of histone demethylases such as lysine demethylase 1 (KDM1) to the DNA (Nair et al. 2010b). The glutamic...the histone H3 arginine methylation status (Mann et al. 2013). Together, these data clearly indicate that PELP1 has a role in the modulation of

  16. Identifying Androgen Receptor-Independent Mechanisms of Prostate Cancer Resistance to Second-Generation Antiandrogen Therapy

    Science.gov (United States)

    2016-08-01

    cancers. 15. SUBJECT TERMS Glucocorticoid Receptor, Serum and glucocorticoid -regulated kinase 1, SGK1, epithelial- mesenchymal transition, EMT 16...receptor transcription factor, glucocorticoid receptor (GR), can activate an overlapping set of AR target genes and can mediate resistance to enzalutamide... glucocorticoid -regulated kinase 1 (SGK1), a target gene of the GR transcriptional program, might be more suitable for targeted inhibition. GR and

  17. A Novel Strategy to Inhibit Hedgehog Signaling and Control Growth of Androgen Independent Prostate Cancer Cells

    Science.gov (United States)

    2013-06-01

    activation) inhibition studies: Conduct western blotting and qRT-PCR for expression of Gli and Gli targets, including Ptch1, FoxL1, SNAIL , TWIST and...isolated for hybridization to Signal Transduction Pathway Finder oligo arrays (SA Biosciences) as described by the manufacturer. The resulting images were

  18. Ferruginol suppresses survival signaling pathways in androgen-independent human prostate cancer cells

    NARCIS (Netherlands)

    de Jesus, Marcelo Bispo; Zambuzzi, Willian Fernando; Ruela de Sousa, Roberta Regina; Areche, Carlos; Santos de Souza, Ana Carolina; Aoyama, Hiroshi; Schmeda-Hirschmann, Guillermo; Rodriguez, Jaime A.; Monteiro de Souza Brito, Alba Regina; Peppelenbosch, Maikel P.; den Hertog, Jeroen; de Paula, Eneida; Ferreira, Carmen Verissima

    Ferruginol, a bioactive compound isolated from a Chilean tree (Podocarpaceae), attracts attention as a consequence of its pharmacological properties, which include anti-fungal, anti-bacterial, cardioprotective, anti-oxidative, anti-plasmodial and anti-ulcerogenic actions. Nevertheless, the molecular

  19. Ferruginol suppresses survival signaling pathways in androgen-independent human prostate cancer cells.

    NARCIS (Netherlands)

    Bispo de Jesus, M.; Zambuzzi, W.F.; Ruela de Sousa, R.R.; Areche, C.; Santos de Souza, A.C.; Aoyama, H.; Schmeda-Hirschmann, G.; Rodriguez, J.A.; Monteiro de Souza Brito, A.R.; Peppelenbosch, M.P.; den Hertog, J.; de Paula, E.; Ferreira, C.V.

    2008-01-01

    Ferruginol, a bioactive compound isolated from a Chilean tree (Podocarpaceae), attracts attention as a consequence of its pharmacological properties, which include anti-fungal, anti-bacterial, cardioprotective, anti-oxidative, anti-plasmodial and anti-ulcerogenic actions. Nevertheless, the molecular

  20. Targeting Ligand-Dependent and Ligand-Independent Androgen Receptor Signaling in Prostate Cancer

    Science.gov (United States)

    2013-10-01

    pathologist. The tissue is then transferred to the laboratory and dissected into 1mm3 fragments. The fragments are then cultured on gelatin sponge submerged in...these interactions may enable shutdown of AR signaling. Methods: Using known crystal structure, modeled structure and imputed structure based...the interactions in Class 1 was based on crystal structures, while those for Class 2 and Class 3 were based on either predicted or imputed (motif in

  1. Cardiovascular mortality in patients with prostate cancer exposed to androgen deprivation therapy.

    Science.gov (United States)

    Monzó-Gardiner, J I; Herranz-Amo, F

    2015-10-01

    A relationship between the administration of GnRH agonists and the risk of acute myocardial infarction (AMC) in patients with prostate cancer has been showed in the third observational study published in April 2014. The association AMC-orchiectomy was not found in any of these studies. Define risk factors for cardiovascular disease in patients treated with GnRH agonist. Their probable underlying pathogenic mechanism in the myocardium and peripheral vascular tree was also analyzed. English articles cited in PubMed were reviewed. No time period is specified. The last search date was 11/30/14. In patients with coronary history of AMC or congestive heart failure, hormonal neoadjuvant therapy increased cardiovascular mortality rates (HR: 1.96, IC 95%: 1.04-3.71; P=.04) as well as cardiovascular-specific mortality rates (AHR: 3.28; IC 95%: 1.01-10.64; P=.048). Two possible mechanisms can be involved: a) direct mechanism through myocardial receptor for GnRH/PKA along with atherogenic plaques; and b) indirect mechanism related with metabolic disturbances. Patients with AMC or congestive heart failure history could present a higher risk of death related to the use of GnRH agonists. In these cases, should carefully consider appropriateness of such treatment. These effects can explained by a direct mechanism on myocardium and peripheral vascular tree and indirect ones related with modified metabolic syndrome. Copyright © 2014 AEU. Publicado por Elsevier España, S.L.U. All rights reserved.

  2. A randomised controlled trial to evaluate the efficacy of a 6 month dietary and physical activity intervention for prostate cancer patients receiving androgen deprivation therapy

    Directory of Open Access Journals (Sweden)

    Haseen Farhana

    2010-08-01

    Full Text Available Abstract Background Treatment with Androgen Deprivation Therapy (ADT for prostate cancer is associated with changes in body composition including increased fat and decreased lean mass; increased fatigue, and a reduction in quality of life. No study to date has evaluated the effect of dietary and physical activity modification on the side-effects related to ADT. The aim of this study is to evaluate the efficacy of a 6-month dietary and physical activity intervention for prostate cancer survivors receiving ADT to minimise the changes in body composition, fatigue and quality of life, typically associated with ADT. Methods Men are recruited to this study if their treatment plan is to receive ADT for at least 6 months. Men who are randomised to the intervention arm receive a home-based tailored intervention to meet the following guidelines a ≥ 5 servings vegetables and fruits/day; b 30%-35% of total energy from fat, and Discussion The results of this study will provide detailed information on diet and physical activity levels in prostate cancer patients treated with ADT and will test the feasibility and efficacy of a diet and physical activity intervention which could provide essential information to develop guidelines for prostate cancer patients to minimise the side effects related to ADT. Trial registration ISRCTN trial number ISCRTN75282423

  3. PSA and androgen-related gene (AR, CYP17, and CYP19) polymorphisms and the risk of adenocarcinoma at prostate biopsy

    DEFF Research Database (Denmark)

    dos Santos, Rodrigo Mattos; de Jesus, Carlos Márcio Nóbrega; Trindade Filho, José Carlos Souza

    2008-01-01

    The aim of the present study was to examine the impact of polymorphisms in prostate-specific antigen (PSA) and androgen-related genes (AR, CYP17, and CYP19) on prostate cancer (PCa) risk in selected high-risk patients who underwent prostate biopsy. Blood samples and prostate tissues were obtained...... for DNA analysis. Single-nucleotide polymorphisms in the 50-untranslated regions (UTRs) of the PSA (substitution A>G at position-158) and CYP17 (substitution T>C at 50-UTR) genes were detected by polymerase chain reaction (PCR)-restriction fragment length polymorphism assays. The CAG and TTTA repeats...... in the AR and CYP19 genes, respectively, were genotyped by PCR-based GeneScan analysis. Patients with the GG genotype of the PSA gene had a higher risk of PCa than those with the AG or AA genotype (OR=3.79, p=0.00138). The AA genotype was associated with lower PSA levels (6.44 +/- 1.64 ng=mL) compared...

  4. Effects of recreational soccer in men with prostate cancer undergoing androgen deprivation therapy: study protocol for the ‘FC Prostate’ randomized controlled trial

    International Nuclear Information System (INIS)

    Uth, Jacob; Brasso, Klaus; Rørth, Mikael; Krustrup, Peter; Midtgaard, Julie; Schmidt, Jakob Friis; Christensen, Jesper Frank; Hornstrup, Therese; Andersen, Lars Juel; Hansen, Peter Riis; Christensen, Karl Bang; Andersen, Lars Louis; Helge, Eva Wulff

    2013-01-01

    Androgen deprivation therapy (ADT) is a cornerstone in the treatment of advanced prostate cancer. Adverse musculoskeletal and cardiovascular effects of ADT are widely reported and investigations into the potential of exercise to ameliorate the effects of treatment are warranted. The ‘Football Club (FC) Prostate’ study is a randomized trial comparing the effects of soccer training with standard treatment approaches on body composition, cardiovascular function, physical function parameters, glucose tolerance, bone health, and patient-reported outcomes in men undergoing ADT for prostate cancer. Using a single-center randomized controlled design, 80 men with histologically confirmed locally advanced or disseminated prostate cancer undergoing ADT for 6 months or more at The Copenhagen University Hospital will be enrolled on this trial. After baseline assessments eligible participants will be randomly assigned to a soccer training group or a control group receiving usual care. The soccer intervention will consist of 12 weeks of training 2–3 times/week for 45–60 min after which the assessment protocol will be repeated. Soccer training will then continue bi-weekly for an additional 20 weeks at the end of which all measures will be repeated to allow for additional analyses of long-term effects. The primary endpoint is changes in lean body mass from baseline to 12 weeks assessed by dual X-ray absorptiometry scan. Secondary endpoints include changes of cardiovascular, metabolic, and physical function parameters, as well as markers of bone metabolism and patient-reported outcomes. The FC Prostate trial will assess the safety and efficacy of a novel soccer-training approach to cancer rehabilitation on a number of clinically important health outcomes in men with advanced prostate cancer during ADT. The results may pave the way for innovative, community-based interventions in the approach to treating prostate cancer. ClinicalTrials.gov: http

  5. Admissions to hospital due to fracture in England in patients with prostate cancer treated with androgen-deprivation therapy - do we have to worry about the hormones?

    Science.gov (United States)

    Jefferies, Edward R; Bahl, Amit; Hounsome, Luke; Eylert, Maike F; Verne, Julia; Persad, Raj A

    2016-09-01

    To investigate the association between androgen-deprivation therapy (ADT) and fracture risk in men with prostate cancer in England. Using the Hospital Episodes Statistics database, which contains all the information about National Health Service (NHS) and NHS-funded hospital admissions in England, for the years 2004-2008, 8 902 patients were found to have had prostate cancer and an admission to hospital with a fracture. Of these patients, 3 372 (37.8%) were identified as being treated with ADT, whilst 5 530 (62.2%) were not. There was a total of 228 852 admissions in the background population. The risk of a fracture requiring hospitalisation increased from 1.12 to 1.41 per 100 person-years in a man with prostate cancer treated with ADT compared with those without ADT, an absolute increase of only 0.29 per 100 person-years. When compared with the background population, there was an increase from 0.58 to 1.41 per 100 person-years, a relative rate ratio increase of 2.4 (P < 0.01) with an absolute increase of 0.83 per 100 person-years. In England there was a small but statistically significant increased risk of fracture in men who had been treated with ADT. Men with prostate cancer, with or without ADT, were at an increased risk of fracture compared with the background population. We therefore suggest that if bone health is to be taken seriously in men with prostate cancer that all these men should be risk assessed (FRAX(®) or Qfracture(®) tools, as National Institute for Health and Care Excellence advised), as all men with prostate cancer have an increased risk of fracture, with those on ADT having slightly higher risk. © 2016 The Authors BJU International © 2016 BJU International Published by John Wiley & Sons Ltd.

  6. The effect of estrogen on the sexual interest of castrated males: Implications to prostate cancer patients on androgen-deprivation therapy.

    Science.gov (United States)

    Wibowo, Erik; Wassersug, Richard J

    2013-09-01

    Androgen deprivation therapy (ADT) for prostate cancer (PCa) treatment causes sexual dysfunction. We review here the effects of estrogen on the sexual performance of androgen-deprived males. The major findings are: 1. Estrogen receptors are present in brain centers that are important for sexual behavior; as well as in male reproductive organs, in a pattern suggesting that estrogen may have some role in orgasmic function and genital skin sensitivity. 2. Estrogen restores sexual interest above castrate levels in many vertebrates including reptiles, birds and mammals; but multiple factors contribute to the magnitude of this effect. 3. Data from castrated men, aromatase-deficient men, male-to-female transsexuals, and men on antiandrogens all suggest that estrogen can maintain some libido in androgen-deprived men. We discuss the general benefits of estrogen therapy to quality of life of men on ADT, the potential risks of this treatment, and possible treatment regimes for estrogen therapy in males. Unless contraindicated, we propose that PCa patients on ADT would benefit from supplemental parenteral estrogen. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  7. Differential regulation of metabolic pathways by androgen receptor (AR) and its constitutively active splice variant, AR-V7, in prostate cancer cells.

    Science.gov (United States)

    Shafi, Ayesha A; Putluri, Vasanta; Arnold, James M; Tsouko, Efrosini; Maity, Suman; Roberts, Justin M; Coarfa, Cristian; Frigo, Daniel E; Putluri, Nagireddy; Sreekumar, Arun; Weigel, Nancy L

    2015-10-13

    Metastatic prostate cancer (PCa) is primarily an androgen-dependent disease, which is treated with androgen deprivation therapy (ADT). Tumors usually develop resistance (castration-resistant PCa [CRPC]), but remain androgen receptor (AR) dependent. Numerous mechanisms for AR-dependent resistance have been identified including expression of constitutively active AR splice variants lacking the hormone-binding domain. Recent clinical studies show that expression of the best-characterized AR variant, AR-V7, correlates with resistance to ADT and poor outcome. Whether AR-V7 is simply a constitutively active substitute for AR or has novel gene targets that cause unique downstream changes is unresolved. Several studies have shown that AR activation alters cell metabolism. Using LNCaP cells with inducible expression of AR-V7 as a model system, we found that AR-V7 stimulated growth, migration, and glycolysis measured by ECAR (extracellular acidification rate) similar to AR. However, further analyses using metabolomics and metabolic flux assays revealed several differences. Whereas AR increased citrate levels, AR-V7 reduced citrate mirroring metabolic shifts observed in CRPC patients. Flux analyses indicate that the low citrate is a result of enhanced utilization rather than a failure to synthesize citrate. Moreover, flux assays suggested that compared to AR, AR-V7 exhibits increased dependence on glutaminolysis and reductive carboxylation to produce some of the TCA (tricarboxylic acid cycle) metabolites. These findings suggest that these unique actions represent potential therapeutic targets.

  8. Optimal duration of androgen deprivation therapy following radiation therapy in intermediate- or high-risk non-metastatic prostate cancer: a systematic review and meta-analysis

    Energy Technology Data Exchange (ETDEWEB)

    Leal, Frederico; Figueiredo, Maximiliano Augusto Novis de; Sasse, Andre Deeke, E-mail: sasse@cevon.com.br [Universidade Estadual de Campinas (UNICAMP), SP (Brazil)

    2015-05-15

    Objectives: to investigate current evidence on the optimal duration of adjuvant hormone deprivation for prostate cancer treated with radiation therapy with curative intent. Materials and Methods: A systematic search was performed in electronic databases. Data from randomized trials comparing different durations of hormone blockade was collected for pooled analysis. Overall survival, disease-free survival, disease-specific survival and toxicity were the outcomes of interest. Meta-analyses were performed using random-effects model. Results: Six studies met the eligibility criteria. For overall survival, the pooled data from the studies demonstrated a statistically significant benefit for longer hormone deprivation (Hazard Ratio 0.84; 95% CI 0.74 - 0.96). A statistically significant benefit was also found for disease-free survival (Hazard Ratio 0.74; 95% CI 0.62 - 0.89), and disease-specific survival (Hazard Ratio 0.73; 95% CI 0.62 - 0.85). Studies with longer blockade duration arm demonstrated greater benefit. Toxicity was low, with no increase in cardiovascular events. Conclusions: Longer duration of androgen deprivation combined to radiotherapy prolongs OS, DFS and DSS in patients with intermediate and high-risk non-metastatic prostate cancer. However, this evidence is based on trials using older radiation techniques, and further research of combination of androgen deprivation and new RT technologies may be warranted. (author)

  9. Combined curative radiotherapy including HDR brachytherapy and androgen deprivation in localized prostate cancer: A prospective assessment of acute and late treatment toxicity

    International Nuclear Information System (INIS)

    Wahlgren, Thomas; Nilsson, Sten; Ryberg, Marianne; Brandberg, Yvonne; Lennernaes, Bo

    2005-01-01

    Self-reported symptoms including urinary, bowel and sexual side effects were investigated prospectively at multiple assessment points before and after combined radiotherapy of prostate cancer including HDR brachytherapy and neoadjuvant androgen deprivation therapy. Between April 2000 and June 2003, patients with predominantly advanced localized prostate tumours subjected to this treatment were asked before treatment and on follow-up visits to complete a questionnaire covering urinary, bowel and sexual problems. The mainly descriptive analyses included 525 patients, responding to at least one questionnaire before or during the period 2-34 months after radiotherapy. Adding androgen deprivation before radiotherapy significantly worsened sexual function. During radiotherapy, urinary, bowel and sexual problems increased and were reported at higher levels up to 34 months, although there seemed to be a general tendency to less pronounced irritative bowel and urinary tract symptoms over time. No side effects requiring surgery were reported. Classic late irradiation effects such as mucosal bleeding were demonstrated mainly during the second year after therapy, but appear less pronounced in comparison with dose escalated EBRT series. In conclusion, despite the high radiation dose given, the toxicity seemed comparable with that of other series but long term (5-10 years) symptom outcome has to be determined

  10. Insulin-like growth factor-binding protein-2 promotes prostate cancer cell growth via IGF-dependent or -independent mechanisms and reduces the efficacy of docetaxel

    Science.gov (United States)

    Uzoh, C C; Holly, J M P; Biernacka, K M; Persad, R A; Bahl, A; Gillatt, D; Perks, C M

    2011-01-01

    Background: The development of androgen independence, chemo-, and radioresistance are critical markers of prostate cancer progression and the predominant reasons for its high mortality. Understanding the resistance to therapy could aid the development of more effective treatments. Aim: The aim of this study is to investigate the effects of insulin-like growth factor-binding protein-2 (IGFBP-2) on prostate cancer cell proliferation and its effects on the response to docetaxel. Methods: DU145 and PC3 cells were treated with IGFBP-2, insulin-like growth factor I (IGF-I) alone or in combination with blockade of the IGF-I receptor or integrin receptors. Cells were also treated with IGFBP-2 short interfering ribonucleic acid with or without a PTEN (phosphatase and tensin homologue deleted on chromosome 10) inhibitor or docetaxel. Tritiated thymidine incorporation was used to measure cell proliferation and Trypan blue cell counting for cell death. Levels of IGFBP-2 mRNA were measured using RT–PCR. Abundance and phosphorylation of proteins were assessed using western immunoblotting. Results: The IGFBP-2 promoted cell growth in both cell lines but with PC3 cells this was in an IGF-dependent manner, whereas with DU145 cells the effect was independent of IGF receptor activation. This IGF-independent effect of IGFBP-2 was mediated by interaction with β-1-containing integrins and a consequent increase in PTEN phosphorylation. We also determined that silencing IGFBP-2 in both cell lines increased the sensitivity of the cells to docetaxel. Conclusion: The IGFBP-2 has a key role in the growth of prostate cancer cells, and silencing IGFBP-2 expression reduced the resistance of these cells to docetaxel. Targeting IGFBP-2 may increase the efficacy of docetaxel. PMID:21487405

  11. Transforming growth factor-β-stimulated clone-22 (TSC-22) is an androgen regulated gene that enhances apoptosis in prostate cancer following IGF-IR inhibition

    Science.gov (United States)

    Sprenger, Cynthia C. T.; Haugk, Kathleen; Sun, Shihua; Coleman, Ilsa; Nelson, Peter S.; Vessella, Robert L.; Ludwig, Dale L.; Wu, Jennifer D.; Plymate, Stephen R.

    2009-01-01

    Purpose Inhibition of IGF signaling using the human IGF-IR monoclonal antibody A12 is most effective at inducing apoptosis in prostate cancer xenografts in the presence of androgen. We undertook this study to determine mechanisms for increased apoptosis by A12 in the presence of androgens. Experimental Methods The castrate-resistant human xenograft LuCaP 35V was implanted into intact or castrate SCID mice and treated with A12 weekly. After six weeks of tumor growth animals were sacrificed and tumors removed and analyzed for cell cycle distribution/apoptosis and cDNA arrays were performed. Results In castrate mice the tumors were delayed in G2 with no apoptosis; in contrast tumors from intact mice underwent apoptosis with either a G1 or G2 delay. TSC-22 was significantly elevated in tumors from the intact mice compared to castrate mice, especially in those tumors with the highest levels of apoptosis. In order to further determine the function of TSC-22, we transfected various human prostate cancer cell lines with a plasmid expressing TSC-22. Cell lines overexpressing TSC-22 demonstrated an increase in apoptosis and a delay in G1. When these cell lines were placed subcutaneously in SCID mice a decreased number of animals formed tumors and the rate of tumor growth was decreased compared to control tumors. Conclusions These data indicate that IGF-IR inhibition in the presence of androgen has an enhanced effect on decreasing tumor growth, in part, through increased expression of the tumor suppressor gene TSC-22. PMID:19996218

  12. Androgen receptor and its splice variant, AR-V7, differentially regulate FOXA1 sensitive genes in LNCaP prostate cancer cells.

    Science.gov (United States)

    Krause, William C; Shafi, Ayesha A; Nakka, Manjula; Weigel, Nancy L

    2014-09-01

    Prostate cancer (PCa) is an androgen-dependent disease, and tumors that are resistant to androgen ablation therapy often remain androgen receptor (AR) dependent. Among the contributors to castration-resistant PCa are AR splice variants that lack the ligand-binding domain (LBD). Instead, they have small amounts of unique sequence derived from cryptic exons or from out of frame translation. The AR-V7 (or AR3) variant is constitutively active and is expressed under conditions consistent with CRPC. AR-V7 is reported to regulate a transcriptional program that is similar but not identical to that of AR. However, it is unknown whether these differences are due to the unique sequence in AR-V7, or simply to loss of the LBD. To examine transcriptional regulation by AR-V7, we have used lentiviruses encoding AR-V7 (amino acids 1-627 of AR with the 16 amino acids unique to the variant) to prepare a derivative of the androgen-dependent LNCaP cells with inducible expression of AR-V7. An additional cell line was generated with regulated expression of AR-NTD (amino acids 1-660 of AR); this mutant lacks the LBD but does not have the AR-V7 specific sequence. We find that AR and AR-V7 have distinct activities on target genes that are co-regulated by FOXA1. Transcripts regulated by AR-V7 were similarly regulated by AR-NTD, indicating that loss of the LBD is sufficient for the observed differences. Differential regulation of target genes correlates with preferential recruitment of AR or AR-V7 to specific cis-regulatory DNA sequences providing an explanation for some of the observed differences in target gene regulation. Copyright © 2014 Elsevier Ltd. All rights reserved.

  13. Partial association of restriction polymorphism of the ligand binding domain of human androgen receptor in prostate cancer

    Directory of Open Access Journals (Sweden)

    Mohamed Hessien

    2016-04-01

    Conclusion: Our results indicate that the loss of the restriction integrity in the C-terminal part (exons: 7 and 8 of the LBD is associated with the progression of benign prostatic hyperplasia to prostate cancer.

  14. The predictive value of ERG protein expression for development of castration-resistant prostate cancer in hormone-naïve advanced prostate cancer treated with primary androgen deprivation therapy

    DEFF Research Database (Denmark)

    Berg, Kasper Drimer; Røder, Martin A; Thomsen, Frederik B

    2015-01-01

    BACKGROUND: Biomarkers predicting response to primary androgen deprivation therapy (ADT) and risk of castration-resistant prostate cancer (CRPC) is lacking. We aimed to analyse the predictive value of ERG expression for development of CRPC. METHODS: In total, 194 patients with advanced and....../or metastatic prostate cancer (PCa) treated with first-line castration-based ADT were included. ERG protein expression was analysed in diagnostic specimens using immunohistochemistry (anti-ERG, EPR3864). Time to CRPC was compared between ERG subgroups using multiple cause-specific Cox regression stratified...... on ERG-status. Risk reclassification and time-dependent area under the ROC curves were used to assess the discriminative ability of ERG-status. Time to PSA-nadir, proportion achieving PSA-nadir ≤0.2 ng/ml, and risk of PCa-specific death were secondary endpoints. RESULTS: Median follow-up was 6.8 years...

  15. Molecular mechanisms of androgen receptor functions

    NARCIS (Netherlands)

    K. Steketee (Karine)

    2007-01-01

    textabstractThe androgens testosterone (T) and dihydrotestosterone (DHT) are steroid hormones, which are necessary for development and maintenance of the functions of the male sex organs, including the prostate. Androgens also play an important role in benign abnormalities of the prostate and in the

  16. [Sexual dysfunctions linked with prostatic diseases].

    Science.gov (United States)

    Rouprêt, M; Seisen, T; De La Taille, A; Desgrandchamps, F

    2012-06-01

    The lower urinary tract symptoms (LUTS) related to benign prostatic hyperplasia (BPH) and the treatment of prostate cancer (PCa) are linked to erectile dysfunction (ED). The objective of this work was to evaluate the influence of prostatic diseases on ED. Data on the influence of BPH and PCa on ED have been explored in Medline and Embase using the MeSH keywords: benign prostatic hyperplasia, prostate cancer, prostatectomy, external beam radiotherapy; androgen deprivation therapy; erectile dysfunction. The articles were selected based on their methodology, relevance, date and language of publication. The rate of ED in patients with BPH ranged from 30 to 70 %. The LUTS were an independent risk factor of ED. The pathophysiology linking BPH to ED has not been elucidated but seems to involve the path of Nitric Oxide - cyclic Guanosine Monophosphate (cGMP-No.), the RhoA - Rho - Kinase (ROCK) signal, the sympathetic autonomic nervous system and pelvic atherosclerosis. The rate of ED after radical prostatectomy (RP) ranged from 60 to 89 %. The bilateral preservation of neurovascular bundels improved these results. Risk factors of ED after RP were age, PSA levels, pretreatment erectile function and surgical technique. The rate of ED after prostate external beam radiotherapy ranged from 6 to 84 %. Risk factors of ED after external beam radiotherapy were age, pretreatment erectile function and association of androgen deprivation therapy. The rate of ED with androgen deprivation therapy was 85 %. Risk factors of ED with androgen deprivation therapy were age > 70 years, diabetes and pretreatment erectile function. Intermittent androgen deprivation therapy was associated with better results on erectile function than continue androgen deprivation therapy. ED is responsible for a decrease of elderly patients life quality already affected by urinary symptoms and prostate disease progression. The development of drugs effective on both ED and BPH or PCa symptoms is then full of

  17. External beam radiation therapy and a low-dose-rate brachytherapy boost without or with androgen deprivation therapy for prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Strom, Tobin J.; Hutchinson, Sean Z.; Shrinath, Kushagra; Cruz, Alex A.; Figura, Nicholas B.; Nethers, Kevin; Biagioli, Matthew C.; Fernandez, Daniel C.; Heysek, Randy V.; Wilder, Richard B., E-mail: richard.wilder@moffitt.org [Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL (United States)

    2014-07-15

    Purpose: To assess outcomes with external beam radiation therapy (EBRT) and a low-dose-rate (LDR) brachytherapy boost without or with androgen deprivation therapy (ADT) for prostate cancer. Materials and Methods: From January 2001 through August 2011, 120 intermediate-risk or high-risk prostate cancer patients were treated with EBRT to a total dose of 4,500 cGy in 25 daily fractions and a palladium-103 LDR brachytherapy boost of 10,000 cGy (n = 90) or an iodine-125 LDR brachytherapy boost of 11,000 cGy (n = 30). ADT, consisting of a gonadotropin-releasing hormone agonist ± an anti-androgen, was administered to 29/92 (32%) intermediate-risk patients for a median duration of 4 months and 26/28 (93%) high-risk patients for a median duration of 28 months. Results: Median follow-up was 5.2 years (range, 1.1-12.8 years). There was no statistically-significant difference in biochemical disease-free survival (bDFS), distant metastasis-free survival (DMFS), or overall survival (OS) without or with ADT. Also, there was no statistically-significant difference in bDFS, DMFS, or OS with a palladium-103 vs. an iodine-125 LDR brachytherapy boost. Conclusions: There was no statistically-significant difference in outcomes with the addition of ADT, though the power of the current study was limited. The Radiation Therapy Oncology Group 0815 and 0924 phase III trials, which have accrual targets of more than 1,500 men, will help to clarify the role ADT in locally-advanced prostate cancer patients treated with EBRT and a brachytherapy boost. Palladium-103 and iodine-125 provide similar bDFS, DMFS, and OS. (author)

  18. Androgen Receptor Modulation Optimized for Response (ARMOR) Phase I and II Studies: Galeterone for the Treatment of Castration-Resistant Prostate Cancer.

    Science.gov (United States)

    Montgomery, Bruce; Eisenberger, Mario A; Rettig, Matthew B; Chu, Franklin; Pili, Roberto; Stephenson, Joseph J; Vogelzang, Nicholas J; Koletsky, Alan J; Nordquist, Luke T; Edenfield, William J; Mamlouk, Khalid; Ferrante, Karen J; Taplin, Mary-Ellen

    2016-03-15

    Galeterone is a selective, multitargeted agent that inhibits CYP17, antagonizes the androgen receptor (AR), and reduces AR expression in prostate cancer cells by causing an increase in AR protein degradation. These open-label phase I and II studies [Androgen Receptor Modulation Optimized for Response-1 (ARMOR1) and ARMOR2 part 1] evaluated the efficacy and safety of galeterone in patients with treatment-naive nonmetastatic or metastatic castration-resistant prostate cancer (CRPC) and established a dose for further study. In ARMOR1, 49 patients received increasing doses (650-2,600 mg) of galeterone in capsule formulation; 28 patients in ARMOR2 part 1 received increasing doses (1,700-3,400 mg) of galeterone in tablet formulation for 12 weeks. Patients were evaluated biweekly for safety and efficacy, and pharmacokinetic parameters were assessed. In ARMOR1, across all doses, 49.0% (24/49) achieved a ≥30% decline in prostate-specific antigen (PSA; PSA30) and 22.4% (11/49) demonstrated a ≥50% PSA decline (PSA50). In ARMOR2 part 1, across all doses, PSA30 was 64.0% (16/25) and PSA50 was 48.0% (12/25). In the 2,550-mg dose cohort, PSA30 was 72.7% (8/11) and PSA50 was 54.5% (6/11). Galeterone was well tolerated; the most common adverse events were fatigue, increased liver enzymes, gastrointestinal events, and pruritus. Most were mild or moderate in severity and required no action and there were no apparent mineralocorticoid excess (AME) events. The efficacy and safety from ARMOR1 and ARMOR2 part 1 and the pharmacokinetic results support the galeterone tablet dose of 2,550 mg/d for further study. Galeterone was well tolerated and demonstrated pharmacodynamic changes consistent with its selective, multifunctional AR signaling inhibition. ©2015 American Association for Cancer Research.

  19. Concurrent deletion of 16q23 and PTEN is an independent prognostic feature in prostate cancer.

    Science.gov (United States)

    Kluth, Martina; Runte, Frederic; Barow, Philipp; Omari, Jazan; Abdelaziz, Zaid M; Paustian, Lisa; Steurer, Stefan; Christina Tsourlakis, Maria; Fisch, Margit; Graefen, Markus; Tennstedt, Pierre; Huland, Hartwig; Michl, Uwe; Minner, Sarah; Sauter, Guido; Simon, Ronald; Adam, Meike; Schlomm, Thorsten

    2015-11-15

    The deletion of 16q23-q24 belongs to the most frequent chromosomal changes in prostate cancer, but the clinical consequences of this alteration have not been studied in detail. We performed fluorescence in situ hybridization analysis using a 16q23 probe in more than 7,400 prostate cancers with clinical follow-up data assembled in a tissue microarray format. Chromosome 16q deletion was found in 21% of cancers, and was linked to advanced tumor stage, high Gleason grade, accelerated cell proliferation, the presence of lymph node metastases (p Deletion was more frequent in ERG fusion-positive (27%) as compared to ERG fusion-negative cancers (16%, p deletions including phosphatase and tensin homolog (PTEN) (p deletion of 16q was linked to early biochemical recurrence independently from the ERG status (p deletion of 16q alone. Multivariate modeling revealed that the prognostic value of 16q/PTEN deletion patterns was independent from the established prognostic factors. In summary, the results of our study demonstrate that the deletion of 16q and PTEN cooperatively drives prostate cancer progression, and suggests that deletion analysis of 16q and PTEN could be of important clinical value particularly for preoperative risk assessment of the clinically most challenging group of low- and intermediated grade prostate cancers. © 2015 UICC.

  20. Three linked nomograms for predicting biochemical failure in prostate cancer treated with radiotherapy plus androgen deprivation therapy

    Energy Technology Data Exchange (ETDEWEB)

    Lopez-Torrecilla, Jose [Hospital General Universitario, Servicio Oncologia Radioterapica- ERESA, Valencia (Spain); Boladeras, Anna [Institut Catala d' Oncologia, S.Oncologia Radioterapica, Hospitalet (Spain); Angeles Cabeza, Maria [Hospital Universitario Doce de Octubre, S.Oncologia Radioterapica, Madrid (Spain); Zapatero, Almudena [Hospital Universitario de la Princesa, S.Oncologia Radioterapica, Madrid (Spain); Jove, Josep [Institut Catala d' Oncologia, S.Oncologia Radioterapica, Badalona (Spain); Esteban, Luis M. [Universidad de Zaragoza, Escuela Universitaria Politecnica de La Almunia, Zaragoza (Spain); Henriquez, Ivan [Hospital Universitari Sant Joan de Reus, S.Oncologia Radioterapica, Reus (Spain); Casana, Manuel; Mengual, Jose Luis [Fundacion Instituto Valenciano de Oncologia, S.Oncologia Radioterapica, Valencia (Spain); Gonzalez-San Segundo, Carmen [Hospital Universitario Gregorio Maranon, S.Oncologia Radioterapica, Madrid (Spain); Gomez-Caamano, Antonio [Hospital Clinico Universitario de Santiago, S.Oncologia Radioterapica, Santiago de Compostela (Spain); Hervas, Asuncion [Hospital Universitario Ramon y Cajal, S.Oncologia Radioterapica, Madrid (Spain); Munoz, Julia Luisa [Hospital Infanta Cristina, S.Oncologia Radioterapica, Badajoz (Spain); Sanz, Gerardo [Universidad de Zaragoza, Departamento de Metodos Estadisticos, Zaragoza (Spain)

    2015-10-15

    Nomograms were established to predict biochemical recurrence (BCR) after radiotherapy (RT) with a low weight of the characteristic variables of RT and androgen deprivation therapy (ADT). Our aim is to provide a new stratified tool for predicting BCR at 4 and 7 years in patients treated using RT with radical intent. A retrospective, nonrandomized analysis was performed on 5044 prostate cancer (PCa) patients with median age 70 years, who received RT - with or without ADT - between November 1992 and May 2007. Median follow-up was 5.5 years. BCR was defined as a rise in serum prostate-specific antigen (PSA) of 2 ng/ml over the post-treatment PSA nadir. Univariate association between predictor variables and BCR was assessed by the log-rank test, and three linked nomograms were created for multivariate prognosis of BCR-free survival. Each nomogram corresponds to a category of the Gleason score - either 6,7, or 8-10 - and all of them were created from a single proportional hazards regression model stratified also by months of ADT (0, 1-6, 7-12, 13-24, 25-36, 36-60). The performance of this model was analyzed by calibration, discrimination, and clinical utility. Initial PSA, clinical stage, and RT dose were significant variables (p < 0.01). The model showed a good calibration. The concordance probability was 0.779, improving those obtained with other nomograms (0.587, 0.571, 0.554) in the database. Survival curves showed best clinical utility in a comparison with National Comprehensive Cancer Network (NCCN) risk groups. For each Gleason score category, the nomogram provides information on the benefit of adding ADT to a specific RT dose. (orig.) [German] Es wurden Nomogramme etabliert, um ein biochemisches Rezidiv (BCR) nach einer Strahlentherapie (RT) vorhersagen zu koennen und den Einfluss der charakteristischen Variablen der RT und der Androgendeprivationstherapie (ADT) dabei moeglichst gering zu halten. Unser Ziel ist es, ein neues stratifiziertes Instrument

  1. Development of an immunotherapeutic adenovirus targeting hormone-independent prostate cancer

    Directory of Open Access Journals (Sweden)

    Kim JS

    2013-11-01

    Full Text Available Jae Sik Kim,1 Sang Don Lee,2 Sang Jin Lee,3 Moon Kee Chung21Department of Urology, The Catholic University of Korea Incheon St Mary's Hospital, Incheon, 2Pusan National University Yangsan Hospital and Research Institute for Convergence of Biomedical Science and Technology, Yangsan, 3Genitourinary Cancer Branch, National Cancer Center, Goyang, KoreaBackground: To develop a targeting therapy for hormone-independent prostate cancer, we constructed and characterized conditionally replicating oncolytic adenovirus (Ad equipped with mRFP(monomeric red fluorescence protein/ttk (modified herpes simplex virus thymidine kinase This construct was then further modified to express both mRFP/ttk and a soluble form of cytokine FLT3L (fms-related tyrosine kinase 3 ligand simultaneously.Methods: To construct the recombinant oncolytic adenovirus, E1a and E4 genes, which are necessary for adenovirus replication, were controlled by the prostate-specific enhancer sequence (PSES targeting prostate cancer cells expressing prostate-specific antigen (PSA and prostate-specific membrane antigen (PSMA. Simultaneously, it expressed the mRFP/ttk fusion protein in order to be able to elicit the cytotoxic effect.Results: The Ad5/35PSES.mRFP/ttk chimeric recombinant adenovirus was generated successfully. When replication of Ad5/35PSES.mRFP/ttk was evaluated in prostate cancer cell lines under fluorescence microscopy, red fluorescence intensity increased more in LNCaP cells, suggesting that the mRFP/ttk fusion protein was folded functionally. In addition, the replication assay including wild-type adenovirus as a positive control showed that PSES-positive cells (LNCaP and CWR22rv permitted virus replication but not PSES-negative cells (DU145 and PC3. Next, we evaluated the killing activity of this recombinant adenovirus. The Ad5/35PSES.mRFP/ttk killed LNCaP and CWR22rv more effectively. Unlike PSES-positive cells, DU145 and PC3 were resistant to killing by this recombinant

  2. Statin Use at the Time of Initiation of Androgen Deprivation Therapy and Time to Progression in Patients With Hormone-Sensitive Prostate Cancer.

    Science.gov (United States)

    Harshman, Lauren C; Wang, Xiaodong; Nakabayashi, Mari; Xie, Wanling; Valenca, Loana; Werner, Lillian; Yu, Yongjiang; Kantoff, Aaron M; Sweeney, Christopher J; Mucci, Lorelei A; Pomerantz, Mark; Lee, Gwo-Shu Mary; Kantoff, Philip W

    2015-07-01

    Statin use has been associated with improved prostate cancer outcomes. Dehydroepiandrosterone sulfate (DHEAS) is a precursor of testosterone and a substrate for SLCO2B1, an organic anionic transporter. We previously demonstrated that genetic variants of SLCO2B1 correlated with time to progression (TTP) during receipt of androgen deprivation therapy (ADT). Statins also use SLCO2B1 to enter cells, and thus we hypothesized that they may compete with DHEAS uptake by the tumor cells. To evaluate whether statin use prolongs TTP during ADT for hormone-sensitive prostate cancer. In vitro studies were performed using prostate cancer cell lines at an academic, comprehensive cancer center. Statin use was retrospectively analyzed in 926 patients who had received ADT for biochemical or metastatic recurrence or de novo metastatic prostate cancer between January 1996 and November 2013. To determine whether statins interfere with DHEAS uptake, we performed in vitro studies using prostate cancer cell lines. Next, we queried our institutional clinical database to assess for an association between statin use and TTP during ADT using multivariable Cox regression analysis and adjusted for known prognostic factors. In vitro, we demonstrated that statins block DHEAS uptake by competitively binding to SLCO2B1. In our ADT cohort of 926 patients, 283 (31%) were taking a statin at ADT initiation. After a median follow-up of 5.8 years, 644 patients (70%) had experienced disease progression while receiving ADT. Median TTP during ADT was 20.3 months (95% CI, 18-24 months). Men taking statins had a longer median TTP during ADT compared with nonusers (27.5 [95% CI, 21.1-37.7] vs 17.4 [95% CI, 14.9-21.1] months; P mechanism to support the clinical observation of prolonged TTP in statin users.

  3. Effects of a Group-Mediated Exercise and Dietary Intervention in the Treatment of Prostate Cancer Patients Undergoing Androgen Deprivation Therapy: Results From the IDEA-P Trial.

    Science.gov (United States)

    Focht, Brian C; Lucas, Alexander R; Grainger, Elizabeth; Simpson, Christina; Fairman, Ciaran M; Thomas-Ahner, Jennifer M; Buell, Jackie; Monk, J Paul; Mortazavi, Amir; Clinton, Steven K

    2018-04-19

    Although androgen-deprivation therapy (ADT) is the foundation of treatment for prostate cancer, the physiological impacts of ADT result in functional decline and enhanced risk of chronic disease and metabolic syndrome. The Individualized Diet and Exercise Adherence Pilot Trial (IDEA-P) is a single-blind, randomized, pilot trial comparing the effects of a group-mediated, cognitive-behavioral (GMCB) exercise and dietary intervention (EX+D) with those of a standard-of-care (SC) control during the treatment of prostate cancer patients undergoing ADT. A total of 32 prostate cancer patients (M age = 66.28, SD = 7.79) undergoing ADT were randomly assigned to the 12-week EX+D intervention (n = 16) or control (n = 16). The primary outcome in IDEA-P was change in mobility performance with secondary outcomes including body composition and muscular strength. Blinded assessment of outcomes were obtained at baseline and at 2- and 3-month follow-ups. Favorable adherence and retention rates were observed, and no serious intervention-related adverse events were documented. Intent-to-treat ANCOVA controlling for baseline value and ADT duration demonstrated that EX+D resulted in significantly greater improvements in mobility performance (p < .02), muscular strength (p < .01), body fat percentage (p < .05), and fat mass (p < .03) at 3-month follow-up, relative to control. Findings from the IDEA-P trial suggest that a GMCB-based EX+D intervention resulted in significant, clinically meaningful improvements in mobility performance, muscular strength, and body composition, relative to controls. Collectively, these results suggest that the EX+D was a safe and well-tolerated intervention for prostate cancer patients on ADT. The utility of implementing this approach in the treatment of prostate cancer patients on ADT should be evaluated in future large-scale efficacy trials. NCT02050906.

  4. A national multicenter phase 2 study of prostate-specific antigen (PSA) pox virus vaccine with sequential androgen ablation therapy in patients with PSA progression: ECOG 9802.

    Science.gov (United States)

    DiPaola, Robert S; Chen, Yu-Hui; Bubley, Glenn J; Stein, Mark N; Hahn, Noah M; Carducci, Michael A; Lattime, Edmund C; Gulley, James L; Arlen, Philip M; Butterfield, Lisa H; Wilding, George

    2015-09-01

    E9802 was a phase 2 multi-institution study conducted to evaluate the safety and effectiveness of vaccinia and fowlpox prostate-specific antigen (PSA) vaccine (step 1) followed by combination with androgen ablation therapy (step 2) in patients with PSA progression without visible metastasis. To test the hypothesis that vaccine therapy in this early disease setting will be safe and have a biochemical effect that would support future studies of immunotherapy in patients with minimal disease burden. Patients who had PSA progression following local therapy were treated with PROSTVAC-V (vaccinia)/TRICOM on cycle 1 followed by PROSTVAC-F (fowlpox)/TRICOM for subsequent cycles in combination with granulocyte-macrophage colony-stimulating factor (step 1). Androgen ablation was added on progression (step 2). Step 1 primary end points included progression at 6 mo and characterization of change in PSA velocity pretreatment to post-treatment. Step 2 end points included PSA response with combined vaccine and androgen ablation. In step 1, 25 of 40 eligible patients (63%) were progression free at 6 mo after registration (90% confidence interval [CI], 48-75). The median pretreatment PSA velocity was 0.13 log(PSA)/mo, in contrast to median postregistration velocity of 0.09 log(PSA)/mo (p=0.02), which is an increase in median PSA doubling time from 5.3 mo to 7.7 mo. No grade ≥4 treatment-related toxicity was observed. In the 27 patients eligible and treated for step 2, 20 patients achieved a complete response (CR) at 7 mo (CR rate: 74%; 90% CI, 57-87). Although supportive of larger studies in the cooperative group setting, this study is limited by the small number of patients and the absence of a control group as in a phase 3 study. A viral PSA vaccine can be administered safely in the multi-institutional cooperative group setting to patients with minimal disease volume alone and combined with androgen ablation, supporting the feasibility of future phase 3 studies in this

  5. beta-TrCP inhibition reduces prostate cancer cell growth via upregulation of the aryl hydrocarbon receptor.

    Directory of Open Access Journals (Sweden)

    Udi Gluschnaider

    2010-02-01

    Full Text Available Prostate cancer is a common and heterogeneous disease, where androgen receptor (AR signaling plays a pivotal role in development and progression. The initial treatment for advanced prostate cancer is suppression of androgen signaling. Later on, essentially all patients develop an androgen independent stage which does not respond to anti hormonal treatment. Thus, alternative strategies targeting novel molecular mechanisms are required. beta-TrCP is an E3 ligase that targets various substrates essential for many aspects of tumorigenesis.Here we show that beta-TrCP depletion suppresses prostate cancer and identify a relevant growth control mechanism. shRNA targeted against beta-TrCP reduced prostate cancer cell growth and cooperated with androgen ablation in vitro and in vivo. We found that beta-TrCP inhibition leads to upregulation of the aryl hydrocarbon receptor (AhR mediating the therapeutic effect. This phenomenon could be ligand independent, as the AhR ligand 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD did not alter prostate cancer cell growth. We detected high AhR expression and activation in basal cells and atrophic epithelial cells of human cancer bearing prostates. AhR expression and activation is also significantly higher in tumor cells compared to benign glandular epithelium.Together these observations suggest that AhR activation may be a cancer counteracting mechanism in the prostate. We maintain that combining beta-TrCP inhibition with androgen ablation could benefit advanced prostate cancer patients.

  6. Red Maca (Lepidium meyenii) did not affect cell viability despite increased androgen receptor and prostate-specific antigen gene expression in the human prostate cancer cell line LNCaP.

    Science.gov (United States)

    Díaz, P; Cardenas, H; Orihuela, P A

    2016-10-01

    We examined whether aqueous extract of Lepidium meyenii (red Maca) could inhibit growth, potentiate apoptotic activity of two anticancer drugs Taxol and 2-methoxyestradiol (2ME) or change mRNA expression for the androgen target genes, androgen receptor (Ar) and prostate-specific antigen (Psa) in the human prostate cancer cell line LNCaP. Red Maca aqueous extract at 0, 10, 20, 40 or 80 μg/ml was added to LNCaP cells, and viability was evaluated by the MTS assay at 24 or 48 hr after treatment. Furthermore, LNCaP cells were treated with 80 μg/ml of red Maca plus Taxol or 2ME 5 μM and viability was assessed 48 hr later. Finally, LNCaP cells were treated with red Maca 0, 20, 40 or 80 μg/ml, and 12 hr later, mRNA level for Ar or Psa was assessed by real-time PCR. Treatment with red Maca did not affect viability of LNCaP cells. Apoptotic activity induced by Taxol and 2ME in LNCaP cells was not altered with red Maca treatment. Relative expression of the mRNA for Ar and Psa increased with red Maca 20 and 40 μg/ml, but not at 80 μg/ml. We conclude that red Maca aqueous extract does not have toxic effects, but stimulates androgen signalling in LNCaP cells. © 2016 Blackwell Verlag GmbH.

  7. Effect of Whole Pelvic Radiotherapy for Patients With Locally Advanced Prostate Cancer Treated With Radiotherapy and Long-Term Androgen Deprivation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Mantini, Giovanna [Department of Radiotherapy, Policlinico Universitario A. Gemelli, Catholic University, Rome (Italy); Tagliaferri, Luca, E-mail: luca.tagliaferri@rm.unicatt.it [Department of Radiotherapy, Policlinico Universitario A. Gemelli, Catholic University, Rome (Italy); Mattiucci, Gian Carlo; Balducci, Mario; Frascino, Vincenzo; Dinapoli, Nicola [Department of Radiotherapy, Policlinico Universitario A. Gemelli, Catholic University, Rome (Italy); Di Gesu, Cinzia; Ippolito, Edy; Morganti, Alessio G. [Department of Radiotherapy, John Paul II Center for High Technology Research and Education in Biomedical Sciences, Catholic University, Campobasso (Italy); Cellini, Numa [Department of Radiotherapy, Policlinico Universitario A. Gemelli, Catholic University, Rome (Italy)

    2011-12-01

    Purpose: To evaluate the effect of whole pelvic radiotherapy (WPRT) in prostate cancer patients treated with RT and long-term (>1 year) androgen deprivation therapy (ADT). Methods and materials: Prostate cancer patients with high-risk features (Stage T3-T4 and/or Gleason score {>=}7 and/or prostate-specific antigen level {>=}20 ng/mL) who had undergone RT and long-term ADT were included in the present analysis. Patients with bowel inflammatory disease, colon diverticula, and colon diverticulitis were excluded from WPRT and treated with prostate-only radiotherapy (PORT). Patients were grouped according to nodal risk involvement as assessed by the Roach formula using different cutoff levels (15%, 20%, 25%, and 30%). Biochemical disease-free survival (bDFS) was analyzed in each group according to the RT type (WPRT or PORT). Results: A total of 358 patients treated between 1994 and 2007 were included in the analysis (46.9% with WPRT and 53.1% with PORT). The median duration of ADT was 24 months (range, 12-38). With a median follow-up of 52 months (range, 20-150), the overall 4-year bDFS rate was 90.5%. The 4-year bDFS rate was similar between the patients who had undergone WPRT or PORT (90.4% vs. 90.5%; p = NS). However, in the group of patients with the greatest nodal risk (>30%), a significant bDFS improvement was recorded for the patients who had undergone WPRT (p = .03). No differences were seen in acute toxicity among the patients treated with WPRT or PORT. The late gastrointestinal toxicity was similar in patients treated with PORT or WPRT (p = NS). Conclusions: Our analysis has supported the use of WPRT in association with long-term ADT for patients with high-risk nodal involvement (>30%), although a definitive recommendation should be confirmed by a randomized trial.

  8. Redefining high-risk prostate cancer based on distant metastases and mortality after high-dose radiotherapy with androgen deprivation therapy.

    Science.gov (United States)

    Tendulkar, Rahul D; Reddy, Chandana A; Stephans, Kevin L; Ciezki, Jay P; Klein, Eric A; Mahadevan, Arul; Kupelian, Patrick A

    2012-03-15

    Modern outcomes of high-dose external beam radiotherapy (EBRT) with androgen deprivation therapy (ADT) for high-risk (HR) prostate cancer are not well described. We identified 585 patients who met HR criteria by 2010 National Comprehensive Cancer Network guidelines, who were treated with EBRT consisting of ≥74 Gy from 1996 to 2008 at Cleveland Clinic, of whom 95% received ADT. We analyzed biochemical relapse-free survival (bRFS), distant metastases-free survival (DMFS), and prostate cancer-specific mortality (PCSM). The median EBRT dose was 78 Gy, and median ADT duration was 6 months. At 10 years, the bRFS was 50.2%, the DMFS was 71.6%, and the PCSM was 14.4%. On multivariate analysis, significant predictors of bRFS were biopsy Gleason score (bGS) of 8 to 10, stage T3, and prostate-specific antigen (PSA) concentration; predictors of DMFS were bGS of 8 to 10 and stage T3; the only predictor of PCSM was bGS of 8 to 10. The duration of ADT was not predictive of any endpoint. We identified an unfavorable high-risk (UHR) group of stage T1-T2 tumors consisting of bGS of 8 with PSA of >10 ng/ml or bGS of 9 to 10 with any PSA level; the remaining clinically localized cancers comprised the favorable high-risk (FHR) group. Comparing FHR, UHR, and stage T3 groups, the DMFS rates were 81.4%, 57.8%, and 59.1% (p bGS of 8 to 10 is the strongest predictor of bRFS, DMFS, and PCSM after high-dose EBRT with ADT. The duration of ADT did not correlate with outcome. Future studies should account for the heterogeneity in HR prostate cancer. Copyright © 2012 Elsevier Inc. All rights reserved.

  9. Cardiovascular Adaptations to Recreational Football Training in Men with Type 2 Diabetes, Untrained Elderly Men and in Men with Prostate Cancer Receiving Androgen Deprivation Therapy

    DEFF Research Database (Denmark)

    Schmidt, Jakob Friis

    untrained men and in veteran football players encouraging results were observed. In conclusion, the present PhD thesis revealed that football training is a feasible alternative exercise training modality, which is associated with improved cardiovascular health in the examined populations.......Numerous people in the general population are not suffuciently physically active and the use of new exercise training modalities which could promote physically active lifestyles are important. The present PhD thesis includes studies , which investigated the effect of recreational football training...... in middle-aged men with type 2 diabetes, 65-75-year-old untrained men, men with prostate cancer receiving androgen deprivation therapy and the effect of life-long participation in football training in veteran football players. The primary purpose was to evaluate the structure and function of the heart...

  10. Effects of Different Exercise Modalities on Fatigue in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy: A Year-long Randomised Controlled Trial.

    Science.gov (United States)

    Taaffe, Dennis R; Newton, Robert U; Spry, Nigel; Joseph, David; Chambers, Suzanne K; Gardiner, Robert A; Wall, Brad A; Cormie, Prue; Bolam, Kate A; Galvão, Daniel A

    2017-08-01

    Physical exercise mitigates fatigue during androgen deprivation therapy (ADT); however, the effects of different exercise prescriptions are unknown. To determine the long-term effects of different exercise modes on fatigue in prostate cancer patients undergoing ADT. Between 2009 and 2012, 163 prostate cancer patients aged 43-90 y on ADT were randomised to exercise targeting the musculoskeletal system (impact loading+resistance training; ILRT; n=58), the cardiovascular and muscular systems (aerobic+resistance training; ART; n=54), or to usual care/delayed exercise (DEL; n=51) for 12 mo across university-affiliated exercise clinics in Australia. Supervised ILRT for 12 mo, supervised ART for 6 mo followed by a 6-mo home program, and DEL received a printed booklet on exercise information for 6 mo followed by 6-mo stationary cycling exercise. Fatigue was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 36 and vitality using the Short Form-36. Analysis of variance was used to compare outcomes for groups at 6 mo and 12 mo. Fatigue was reduced (p=0.005) in ILRT at 6 mo and 12 mo (∼5 points), and in ART (p=0.005) and DEL (p=0.022) at 12 mo. Similarly, vitality increased for all groups (p≤0.001) at 12 mo (∼4 points). Those with the highest levels of fatigue and lowest vitality improved the most with exercise (p trend exercise modes have comparable effects on reducing fatigue and enhancing vitality during ADT. Patients with the highest levels of fatigue and lowest vitality had the greatest benefits. We compared the effects of different exercise modes on fatigue in men on androgen deprivation therapy. All exercise programs reduced fatigue and enhanced vitality. We conclude that undertaking some form of exercise will help reduce fatigue, especially in those who are the most fatigued. Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.

  11. Alterations of androgen receptor-regulated enhancer RNAs (eRNAs) contribute to enzalutamide resistance in castration-resistant prostate cancer.

    Science.gov (United States)

    Zhao, Jingwen; Zhao, Yu; Wang, Liguo; Zhang, Jun; Karnes, R Jeffrey; Kohli, Manish; Wang, Guixia; Huang, Haojie

    2016-06-21

    Enzalutamide is a second-generation anti-androgen for treatment of castration-resistant prostate cancer (CPRC). It prolongs survival of CRPC patients, but its overall survival benefit is relatively modest (4.8 months) and by 24 months most patients progress on enzalutamide. To date, however, the molecular mechanisms underlying enzalutamide resistance remain elusive. Herein, we report enzalutamide treatment-induced alterations of androgen receptor (AR)-regulated enhancer RNAs (AR-eRNAs) and their roles in enzalutamide-resistant growth and survival of CRPC cells. AR chromatin immunoprecipitation and high throughput sequencing (ChIP-seq) and RNA-seq analyses revealed that 188 and 227 AR-eRNAs were differentially expressed in enzalutamide-resistant LNCaP and C4-2 cells, respectively. The AR-eRNAs upregulated in C4-2 cells and downregulated in LNCaP cells were selected through meta-analysis. Expression of AR-eRNAs and related mRNAs in the loci of FTO, LUZP2, MARC1 and NCAM2 were further verified by real-time RT-PCR. Silencing of LUZP2 inhibited, but silencing of MARC1 increased the growth of enzalutamide-resistant C4-2 cells. Intriguingly, meta-analysis showed that expression of LUZP2 mRNA increased in primary tumors compared to normal prostate tissues, but decreased again in metastatic CRPC. Our findings suggest that eRNA alteration profiling is a viable new approach to identify functional gene loci that may not only contribute to enzalutamide-resistant growth of CRPC, but also serve as new targets for CRPC therapy.

  12. Prostate cancer risk prediction using the novel versions of the European Randomised Study for Screening of Prostate Cancer (ERSPC) and Prostate Cancer Prevention Trial (PCPT) risk calculators: independent validation and comparison in a contemporary European cohort.

    Science.gov (United States)

    Poyet, Cédric; Nieboer, Daan; Bhindi, Bimal; Kulkarni, Girish S; Wiederkehr, Caroline; Wettstein, Marian S; Largo, Remo; Wild, Peter; Sulser, Tullio; Hermanns, Thomas

    2016-03-01

    To externally validate and compare the two novel versions of the European Randomised Study for Screening of Prostate Cancer (ERSPC)-prostate cancer risk calculator (RC) and Prostate Cancer Prevention Trial (PCPT)-RC. All men who underwent a transrectal prostate biopsy in a European tertiary care centre between 2004 and 2012 were retrospectively identified. The probability of detecting prostate cancer and significant cancer (Gleason score ≥7) was calculated for each man using the novel versions of the ERSPC-RC (DRE-based version 3/4) and the PCPT-RC (version 2.0) and compared with biopsy results. Calibration and discrimination were assessed using the calibration slope method and the area under the receiver operating characteristic curve (AUC), respectively. Additionally, decision curve analyses were performed. Of 1 996 men, 483 (24%) were diagnosed with prostate cancer and 226 (11%) with significant prostate cancer. Calibration of the two RCs was comparable, although the PCPT-RC was slightly superior in the higher risk prediction range for any and significant prostate cancer. Discrimination of the ERSPC- and PCPT-RC was comparable for any prostate cancer (AUCs 0.65 vs 0.66), while the ERSPC-RC was somewhat better for significant prostate cancer (AUCs 0.73 vs 0.70). Decision curve analyses revealed a comparable net benefit for any prostate cancer and a slightly greater net benefit for significant prostate cancer using the ERSPC-RC. In our independent external validation, both updated RCs showed less optimistic performance compared with their original reports, particularly for the prediction of any prostate cancer. Risk prediction of significant prostate cancer, which is important to avoid unnecessary biopsies and reduce over-diagnosis and overtreatment, was better for both RCs and slightly superior using the ERSPC-RC. © 2015 The Authors BJU International © 2015 BJU International Published by John Wiley & Sons Ltd.

  13. Long-term outcomes from dose-escalated image-guided intensity-modulated radiotherapy with androgen deprivation: encouraging results for intermediate- and high-risk prostate cancer

    Directory of Open Access Journals (Sweden)

    Wilcox SW

    2014-08-01

    Full Text Available Shea W Wilcox,1,4 Noel J Aherne,2,4 Linus C Benjamin,1 Bosco Wu,1 Thomaz de Campos Silva,3 Craig S McLachlan,4 Michael J McKay,3,5 Andrew J Last,1 Thomas P Shakespeare1–4 1North Coast Cancer Institute, Port Macquarie, NSW, Australia; 2North Coast Cancer Institute, Coffs Harbour, NSW, Australia; 3North Coast Cancer Institute, Lismore, NSW, Australia; 4The University of New South Wales, Rural Clinical School, Sydney, NSW, Australia; 5The University of Sydney, Sydney, NSW, Australia Purpose: Dose-escalated (DE radiotherapy in the setting of localized prostate cancer has been shown to improve biochemical disease-free survival (bDFS in several studies. In the same group of patients, androgen deprivation therapy (ADT has been shown to confer a survival benefit when combined with radiotherapy doses of up to 70 Gy; however, there is currently little long-term data on patients who have received high-dose intensity-modulated radiotherapy (IMRT with ADT. We report the long-term outcomes in a large cohort of patients treated with the combination of DE image-guided IMRT (IG-IMRT and ADT. Methods and materials: Patients with localized prostate cancer were identified from a centralized database across an integrated cancer center. All patients received DE IG-IMRT, combined with ADT, and had a minimum follow up of 12 months post-radiotherapy. All relapse and toxicity data were collected prospectively. Actuarial bDFS, metastasis-free survival, prostate cancer-specific survival, and multivariate analyses were calculated using the SPSS v20.0 statistical package. Results: Seven hundred and eighty-two eligible patients were identified with a median follow up of 46 months. Overall, 4.3% of patients relapsed, 2.0% developed distant metastases, and 0.6% died from metastatic prostate cancer. At 5-years, bDFS was 88%, metastasis-free survival was 95%, and prostate cancer-specific survival was 98%. Five-year grade 2 genitourinary and gastrointestinal toxicity was 2

  14. Patterns of Declining Use and the Adverse Effect of Primary Androgen Deprivation on All-cause Mortality in Elderly Men with Prostate Cancer.

    Science.gov (United States)

    Sammon, Jesse D; Abdollah, Firas; Reznor, Gally; Pucheril, Daniel; Choueiri, Toni K; Hu, Jim C; Kim, Simon P; Schmid, Marianne; Sood, Akshay; Sun, Maxine; Kibel, Adam S; Nguyen, Paul L; Menon, Mani; Trinh, Quoc-Dien

    2015-07-01

    Primary androgen deprivation therapy (pADT) is commonly used to treat elderly men diagnosed with localized prostate cancer (CaP), despite the lack of evidence supporting its use. To examine the effect of pADT on mortality and to assess contemporary trends of pADT use in elderly men with CaP. Men older than 65 yr residing in Surveillance, Epidemiology, and End Results (SEER) registry areas diagnosed with localized or locally advanced CaP between 1992 and 2009 and not receiving definitive therapy. Propensity score (PS)-weighted Cox proportional hazards models were used to estimate the effect of pADT use on overall survival among patients receiving pADT. The interaction between comorbidity-adjusted life expectancy (LE) and pADT use was assessed within the Cox and PS-weighted models. Contemporary (2004-2009) trends for pADT use were analyzed by linear regression. The primary cohort included 46 376 men, of whom 17 873 received pADT (39%). Patients with >10 yr LE had lower pADT utilization rates than patients with short LE. Between 2004 and 2009, the use of pADT in men with localized CaP decreased by 14% (from 36% to 22%). Relative to observation, pADT was associated with a survival disadvantage, with a hazard ratio for all-cause mortality of 1.37 (95% confidence interval 1.20-1.56). Limitations included biases not accounted for by the PS-weighted model, changes in CaP staging over the study period, the absence of prostate-specific antigen (PSA) data prior to 2004, and the limits of retrospective analysis to demonstrate causality. The use of pADT in elderly men with localized CaP has decreased over time. For men forgoing primary definitive therapy, the use of pADT is not associated with a survival benefit compared to observation, and denies men an opportunity for cure with definitive therapy. The deleterious effect of pADT is most pronounced in men with prolonged LE. In this report, we assessed the effect of primary androgen deprivation (pADT) on prostate cancer

  15. Ezrin mediates c-Myc actions in prostate cancer cell invasion

    DEFF Research Database (Denmark)

    Chuan, Yin Choy; Iglesias Gato, Diego; Fernandez-Perez, L

    2010-01-01

    The forced overexpression of c-Myc in mouse prostate and in normal human prostate epithelial cells results in tumor transformation with an invasive phenotype. How c-Myc regulates cell invasion is poorly understood. In this study, we have investigated the interplay of c-Myc and androgens...... in the regulation of prostate cancer cell invasion. We found that c-Myc induces cell invasion and anchorage-independent growth by regulating ezrin protein expression in the presence of androgens. The activity of the ezrin promoter is controlled by androgens through c-Myc, which binds to a phylogenetically conserved...... E-Box located in the proximal promoter region. Besides, we also show that ezrin is an important regulator of c-Myc protein levels. These effects are achieved through androgen-induced changes in ezrin phosphorylation, which results in the regulation of downstream signals. These downstream signals...

  16. Intensity-Modulated Radiotherapy Reduces Gastrointestinal Toxicity in Patients Treated With Androgen Deprivation Therapy for Prostate Cancer

    International Nuclear Information System (INIS)

    Sharma, Navesh K.; Li Tianyu; Chen, David Y.; Pollack, Alan; Horwitz, Eric M.; Buyyounouski, Mark K.

    2011-01-01

    Purpose: Androgen deprivation therapy (AD) has been shown to increase late Grade 2 or greater rectal toxicity when used concurrently with three-dimensional conformal radiotherapy (3D-CRT). Intensity-modulated radiotherapy (IMRT) has the potential to reduce toxicity by limiting the radiation dose received by the bowel and bladder. The present study compared the genitourinary and gastrointestinal (GI) toxicity in men treated with 3D-CRT+AD vs. IMRT+AD. Methods and Materials: Between July 1992 and July 2004, 293 men underwent 3D-CRT (n = 170) or IMRT (n = 123) with concurrent AD (<6 months, n = 123; ≥6 months, n = 170). The median radiation dose was 76 Gy for 3D-CRT (International Commission on Radiation Units and Measurements) and 76 Gy for IMRT (95% to the planning target volume). Toxicity was assessed by a patient symptom questionnaire that was completed at each visit and recorded using a Fox Chase Modified Late Effects Normal Tissue Task radiation morbidity scale. Results: The mean follow-up was 86 months (standard deviation, 29.3) for the 3D-CRT group and 40 months (standard deviation, 9.7) for the IMRT group. Acute GI toxicity (odds ratio, 4; 95% confidence interval, 1.6-11.7; p = .005) was significantly greater with 3D-CRT than with IMRT and was independent of the AD duration (i.e., <6 vs. ≥6 months). The interval to the development of late GI toxicity was significantly longer in the IMRT group. The 5-year Kaplan-Meier estimate for Grade 2 or greater GI toxicity was 20% for 3D-CRT and 8% for IMRT (p = .01). On multivariate analysis, Grade 2 or greater late GI toxicity (hazard ratio, 2.1; 95% confidence interval, 1.1-4.3; p = .04) was more prevalent in the 3D-CRT patients. Conclusion: Compared with 3D-CRT, IMRT significantly decreased the acute and late GI toxicity in patients treated with AD.

  17. The Role of (BETA)-Catenin in Androgen Receptor Signaling

    National Research Council Canada - National Science Library

    Bhowmick, Neil A

    2006-01-01

    .... Our preliminary data seem indicate stromally derived paracrine Wnt family members activate theepithelial frizzled receptor to enable prostate epithelial survival in an androgen deficient environment...

  18. Expanding the therapeutic use of androgens via selective androgen receptor modulators (SARMs)

    OpenAIRE

    Gao, Wenqing; Dalton, James T.

    2007-01-01

    Selective androgen receptor modulators (SARMs) are a novel class of androgen receptor (AR) ligands that might change the future of androgen therapy dramatically. With improved pharmacokinetic characteristics and tissue-selective pharmacological activities, SARMs are expected to greatly extend the clinical applications of androgens to osteoporosis, muscle wasting, male contraception and diseases of the prostate. Mechanistic studies with currently available SARMs will help to define the contrib...

  19. Ultrasound-Based Characterization of Prostate Cancer Using Joint Independent Component Analysis.

    Science.gov (United States)

    Imani, Farhad; Ramezani, Mahdi; Nouranian, Saman; Gibson, Eli; Khojaste, Amir; Gaed, Mena; Moussa, Madeleine; Gomez, Jose A; Romagnoli, Cesare; Leveridge, Michael; Chang, Silvia; Fenster, Aaron; Siemens, D Robert; Ward, Aaron D; Mousavi, Parvin; Abolmaesumi, Purang

    2015-07-01

    This paper presents the results of a new approach for selection of RF time series features based on joint independent component analysis for in vivo characterization of prostate cancer. We project three sets of RF time series features extracted from the spectrum, fractal dimension, and the wavelet transform of the ultrasound RF data on a space spanned by five joint independent components. Then, we demonstrate that the obtained mixing coefficients from a group of patients can be used to train a classifier, which can be applied to characterize cancerous regions of a test patient. In a leave-one-patient-out cross validation, an area under receiver operating characteristic curve of 0.93 and classification accuracy of 84% are achieved. Ultrasound RF time series can be used to accurately characterize prostate cancer, in vivo without the need for exhaustive search in the feature space. We use joint independent component analysis for systematic fusion of multiple sets of RF time series features, within a machine learning framework, to characterize PCa in an in vivo study.

  20. Development of a nomogram model predicting current bone scan positivity in patients treated with androgen-deprivation therapy for prostate cancer

    Directory of Open Access Journals (Sweden)

    Michael eKattan

    2014-10-01

    Full Text Available Purpose: To develop a nomogram predictive of current bone scan positivity in patients receiving androgen-deprivation therapy (ADT for advanced prostate cancer; to augment clinical judgment and highlight patients in need of additional imaging investigations.Materials and Methods: A retrospective chart review of bone scan records (conventional 99mTc-scintigraphy of 1,293 patients who received ADT at the Memorial Sloan-Kettering Cancer Center from 2000 to 2011. Multivariable logistic regression analysis was used to identify variables suitable for inclusion in the nomogram. The probability of current bone scan positivity was determined using these variables and the predictive accuracy of the nomogram was quantified by concordance index.Results: In total, 2,681 bone scan records were analyzed and 636 patients had a positive result. Overall, the median pre-scan prostate-specific antigen (PSA level was 2.4 ng/ml; median PSA doubling time (PSADT was 5.8 months. At the time of a positive scan, median PSA level was 8.2 ng/ml; 53% of patients had PSA <10 ng/ml; median PSADT was 4.0 months. Five variables were included in the nomogram: number of previous negative bone scans after initiating ADT, PSA level, Gleason grade sum, and history of radical prostatectomy and radiotherapy. A concordance index value of 0.721 was calculated for the nomogram. This was a retrospective study based on limited data in patients treated in a large cancer centre who underwent conventional 99mTc bone scans, which themselves have inherent limitations. Conclusions: This is the first nomogram to predict current bone scan positivity in ADT-treated prostate cancer patients, providing high predictive accuracy.

  1. Lack of benefit for the addition of androgen deprivation therapy to dose-escalated radiotherapy in the treatment of intermediate- and high-risk prostate cancer.

    LENUS (Irish Health Repository)

    Krauss, Daniel

    2012-02-01

    PURPOSE: Assessment of androgen deprivation therapy (ADT) benefits for prostate cancer treated with dose-escalated radiotherapy (RT). METHODS AND MATERIALS: From 1991 to 2004, 1,044 patients with intermediate- (n = 782) or high-risk (n = 262) prostate cancer were treated with dose-escalated RT at William Beaumont Hospital. Patients received external-beam RT (EBRT) alone, brachytherapy (high or low dose rate), or high dose rate brachytherapy plus pelvic EBRT. Intermediate-risk patients had Gleason score 7, prostate-specific antigen (PSA) 10.0-19.9 ng\\/mL, or Stage T2b-T2c. High-risk patients had Gleason score 8-10, PSA >\\/=20, or Stage T3. Patients were additionally divided specifically by Gleason score, presence of palpable disease, and PSA level to further define subgroups benefitting from ADT. RESULTS: Median follow-up was 5 years; 420 patients received ADT + dose-escalated RT, and 624 received dose-escalated RT alone. For all patients, no advantages in any clinical endpoints at 8 years were associated with ADT administration. No differences in any endpoints were associated with ADT administration based on intermediate- vs. high-risk group or RT modality when analyzed separately. Patients with palpable disease plus Gleason >\\/=8 demonstrated improved clinical failure rates and a trend toward improved survival with ADT. Intermediate-risk patients treated with brachytherapy alone had improved biochemical control when ADT was given. CONCLUSION: Benefits of ADT in the setting of dose-escalated RT remain poorly defined. This question must continue to be addressed in prospective study.

  2. Use of 5-alpha-reductase inhibitors as alternatives to luteinizing-hormone releasing hormone (LHRH) analogs or anti-androgens for prostate downsizing before brachytherapy.

    Science.gov (United States)

    Bae, Hee Joon; Mian, Omar; Vaidya, Dhananjay; DeWeese, Theodore L; Song, Daniel Y

    2017-10-10

    Prostate hypertrophy, median lobe hypertrophy, and pubic arch interference (PAI) are relative contraindications to brachytherapy because of potential morbidity and technical considerations. GnRH analogs or non-steroidal anti-androgens are currently utilized to achieve prostatic downsizing prior to brachytherapy. However, such agents have been associated with effects on body habitus, metabolism, and quality of life. In contrast, 5-alpha reductase inhibitors (5-ARI) are far less frequently associated with these morbidities. Patients with large gland size, median lobe hypertrophy, or PAI were offered 5-ARI therapy. Repeat transrectal ultrasound was performed at 3 or 4 months, followed by brachytherapy if resolution was achieved. If downsizing was inadequate, patients were offered continuation of 5-ARI for additional 3 months, gonadotropin-releasing hormone analog (GnRH) agonist or antiandrogen therapy, or other curative treatment. Of 59 patients with follow-up available, 42 (71%) were deemed to have adequate downsizing; 37 (63%) after 3 to 4 months of 5-ARI and 5 (8%) after 7 to 8 months. Seventeen patients (29%) received other treatments because of inadequate effect. Median volume reduction was 20%. Of 41 patients undergoing brachytherapy, 4 (9.7%) required temporary catheterization because of obstruction. Median follow-up after implantation was 25 months (range, 1-64). Median time for return to International Prostate Symptom Score ≤5 of baseline score was 7 months (interquartile ratio, 6-13). All but 1 patient who received brachytherapy remain biochemically controlled. 5-ARI monotherapy is an alternative for downsizing in patients with hypertrophy or PAI, with more than 70% achieving adequate downsizing without use of GnRH analogs or antiandrogens. Patients who received brachytherapy experienced typical rates of postimplant urinary morbidity. Copyright © 2017. Published by Elsevier Inc.

  3. End-of-radiation PSA as a novel prognostic factor in patients undergoing definitive radiation and androgen deprivation therapy for prostate cancer.

    Science.gov (United States)

    Narang, A K; Trieu, J; Radwan, N; Ram, A; Robertson, S P; He, P; Gergis, C; Griffith, E; Singh, H; DeWeese, T A; Honig, S; Annadanam, A; Greco, S; DeVille, C; McNutt, T; DeWeese, T L; Song, D Y; Tran, P T

    2017-06-01

    In men undergoing definitive radiation for prostate cancer, it is unclear whether early biochemical response can provide additional prognostic value beyond pre-treatment risk stratification. Prostate cancer patients consecutively treated with definitive radiation at our institution by a single provider from 1993 to 2006 and who had an end-of-radiation (EOR) PSA (n=688, median follow-up 11.2 years). We analyzed the association of an EOR PSA level, obtained during the last week of radiation, with survival outcomes. Multivariable-adjusted cox proportional hazards models were constructed to assess associations between a detectable EOR PSA (defined as ⩾0.1 ng ml -1 ) and biochemical failure-free survival (BFFS), metastasis-free survival (MFS), prostate cancer-specific survival (PCSS) and overall survival (OS). Kaplan-Meier survival curves were constructed, with stratification by EOR PSA. At the end of radiation, the PSA level was undetectable in 30% of patients. Men with a detectable EOR PSA experienced inferior 10-year BFFS (49.7% versus 64.4%, PPSA. Among National Comprehensive Care Network (NCCN) intermediate- and high-risk men who were treated with definitive radiation and androgen deprivation therapy (ADT), a detectable EOR PSA was more strongly associated with PCSS than initial NCCN risk level (EOR PSA: HR 5.89, 95% CI 2.37-14.65, PPSA was significantly associated with survival endpoints in men who received treatment with definitive radiation and ADT. Whether the EOR PSA can be used to modulate treatment intensity merits further investigation.

  4. A Phase 1/2 Trial of Brief Androgen Suppression and Stereotactic Radiation Therapy (FASTR) for High-Risk Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Bauman, Glenn, E-mail: Glenn.bauman@lhsc.on.ca [Division of Radiation Oncology, Department of Oncology, Western University and London Regional Cancer Program, London, Ontario (Canada); Ferguson, Michelle [Department of Radiation Oncology, Allan Blair Cancer Centre, Regina, Saskatchewan (Canada); Lock, Michael; Chen, Jeff; Ahmad, Belal; Venkatesan, V.M.; Sexton, Tracy; D' Souza, David [Division of Radiation Oncology, Department of Oncology, Western University and London Regional Cancer Program, London, Ontario (Canada); Loblaw, Andrew [Department of Radiation Medicine, University of Toronto and Odette Cancer Center, Toronto, Ontario (Canada); Warner, Andrew; Rodrigues, George [Division of Radiation Oncology, Department of Oncology, Western University and London Regional Cancer Program, London, Ontario (Canada)

    2015-07-15

    Purpose: To initiate a phase 1/2 trial to examine the tolerability of a condensed combined-modality protocol for high-risk prostate cancer. Methods and Materials: Men scoring ≥3 on the Vulnerable Elderly Scale (VES) or refusing conventionally fractionated treatment for high-risk prostate cancer were eligible to participate. Androgen suppression was delivered for 12 months, and radiation therapy was delivered using 25 Gy to pelvic nodes delivered synchronously with 40 Gy to the prostate given as 1 fraction per week over 5 weeks. The phase 1 component included predetermined stopping rules based on 6-month treatment-related toxicity, with trial suspension specified if there were ≥6 of 15 patients (40%) or ≥3 of 15 (20%) who experienced grade ≥2 or ≥3 gastrointestinal (GI) or genitourinary (GU) toxicity, respectively. Results: Sixteen men were enrolled, with 7 men meeting the criteria of VES ≥3 and 9 men having a VES <3 but choosing the condensed treatment. One man was not treated owing to discovery of a synchronous primary rectal cancer. Four patients (26%) experienced grade ≥2 toxicity at 6 weeks after treatment. There were 9 of 15 (60%) who experienced grade ≥2 GI or GU toxicity and 4 of 15 (26%) grade ≥3 GI or GU toxicity at 6 months, and 5 of 15 (30%) grade ≥2 GI and GU toxicity at 6 months. A review of the 15 cases did not identify any remedial changes, thus the phase 1 criteria were not met. Conclusion: This novel condensed treatment had higher than anticipated late toxicities and was terminated before phase 2 accrual. Treatment factors, such as inclusion of pelvic lymph node radiation therapy, planning constraints, and treatment margins, or patient factors related to the specific frail elderly population may be contributing.

  5. Lack of Apparent Survival Benefit With Use of Androgen Deprivation Therapy in Patients With High-risk Prostate Cancer Receiving Combined External Beam Radiation Therapy and Brachytherapy.

    Science.gov (United States)

    Yang, David D; Muralidhar, Vinayak; Mahal, Brandon A; Nguyen, Paul L; Devlin, Phillip M; King, Martin T; Orio, Peter F

    2018-01-01

    Although level 1 evidence has demonstrated a survival benefit from the addition of androgen deprivation therapy (ADT) to external beam radiation therapy (EBRT) for patients with high-risk prostate cancer, the benefits of ADT with combined EBRT and brachytherapy for high-risk patients are unclear. We examined the association between ADT and overall survival in a national cohort of high-risk patients treated with EBRT with or without brachytherapy. We identified 46,325 men in the National Cancer Database with a diagnosis of high-risk prostate cancer (Gleason score 8-10, clinical stage T3-T4, or prostate-specific antigen >20 ng/mL) who were treated with EBRT with or without brachytherapy and ADT from 2004 through 2011. Multivariable Cox regression analysis adjusting for sociodemographic and clinicopathologic factors was used to identify the association between ADT and overall survival. The median follow-up period was 48.6 and 59.2 months for patients treated with EBRT only and combined modality RT, respectively. ADT was associated with an improvement in overall survival for the 85.0% (39,361) of the study cohort who underwent EBRT alone (adjusted hazard ratio 0.91, P=.001) but not for patients treated with combined modality RT (adjusted hazard ratio 1.05, P=.496), with a significant interaction (P interaction =.036). In contrast to the known survival benefit when ADT is given with EBRT, our results suggest that ADT might not improve survival for high-risk patients who undergo combined EBRT and brachytherapy. Given the significant adverse effects of ADT, in particular, with long-term therapy, a randomized controlled trial of combined EBRT and brachytherapy with or without ADT for select high-risk patients using a noninferiority design should be undertaken. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. High-Dose Radiotherapy With or Without Androgen Deprivation Therapy for Intermediate-Risk Prostate Cancer: Cancer Control and Toxicity Outcomes

    Energy Technology Data Exchange (ETDEWEB)

    Edelman, Scott [Department of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, GA (United States); Liauw, Stanley L. [Department of Radiation Oncology, University of Chicago, Chicago, IL (United States); Rossi, Peter J.; Cooper, Sherrie [Department of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, GA (United States); Jani, Ashesh B., E-mail: abjani@emory.edu [Department of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, GA (United States)

    2012-08-01

    Purpose: To evaluate the impact of short-course androgen deprivation therapy (ADT) on cancer control outcomes and toxicity in intermediate-risk prostate cancer treated with dose-escalated external beam radiotherapy (high-dose radiotherapy [HDRT]). Methods and Materials: Demographic, disease, and treatment characteristics of prostate cancer patients at 2 institution consortiums were charted. Of 296 men with intermediate-risk prostate cancer (defined as {>=}T2b, prostate-specific antigen level >10 ng/mL, or Gleason score [GS] of 7, with none of the following: {>=}T3, prostate-specific antigen level >20 ng/mL, GS {>=}8, or positive nodes) treated with HDRT to a dose of 72 Gy or greater, 123 received short-course ADT and 173 did not. Univariate and multivariate analyses on biochemical failure-free survival (BFFS) (including subset analysis by disease factors) and on overall survival (OS) were performed, as were comparisons of gastrointestinal (GI) and genitourinary (GU) toxicity rates. Results: For the whole group, the median dose was 75.6 Gy; the minimum follow-up was 2 years, and the median follow-up was 47.4 months. For ADT vs. no ADT, the 5-year BFFS rate was 86% vs. 79% (p = 0.138) and the 5-year OS rate was 87% vs. 80% (p = 0.159). On multivariate analysis, percent positive cores (PPC) (p = 0.002) and GS (p = 0.008) were significantly associated with BFFS, with ADT showing a trend (p = 0.055). The impact of ADT was highest in the subsets with PPC greater than 50% (p = 0.019), GS 4+3 (p = 0.078), and number of risk factors greater than 1 (p = 0.022). Only intensity-modulated radiotherapy use (p = 0.012) and GS (p = 0.023) reached significance for OS, and there were no significant differences in GU or GI toxicity. Conclusions: Although the use of ADT with HDRT did not influence BFFS, our study suggests a benefit in patients with PPC greater than 50%, GS 4+3, or multiple risk factors. No OS benefit was shown, and ADT was not associated with additional radiotherapy

  7. Phase II Study of Long-Term Androgen Suppression With Bevacizumab and Intensity-Modulated Radiation Therapy (IMRT) in High-Risk Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Vuky, Jacqueline, E-mail: vukyja@ohsu.edu [Section of Community Hematology/Oncology, Knight Cancer Institute, Oregon Health Sciences University, Portland, OR (United States); Pham, Huong T. [Section of Hematology/Oncology and Radiation Oncology, Virginia Mason Medical Center, Seattle, WA (United States); Warren, Sarah; Douglass, Erika [Benaroya Research Institute, Virginia Mason Medical Center, Seattle, WA (United States); Badiozamani, Kasra [Section of Hematology/Oncology and Radiation Oncology, Virginia Mason Medical Center, Seattle, WA (United States); Madsen, Berit; Hsi, Alex [Peninsula Cancer Center, Poulsbo, WA (United States); Song Guobin [Section of Hematology/Oncology and Radiation Oncology, Virginia Mason Medical Center, Seattle, WA (United States)

    2012-03-15

    Purpose: We report a Phase II trial assessing the acute and late toxicities of intensity-modulated radiation therapy (IMRT), long-term androgen suppression (LTAS), and bevacizumab in patients with high-risk localized prostate cancer. Methods and Materials: We treated 18 patients with LTAS with bicalutamide and goserelin in combination with bevacizumab and IMRT. Bevacizumab (10 mg/kg every 2 weeks) was administered for the first 16 weeks, and 15 mg/kg was then given every 3 weeks for 12 additional weeks, with an IMRT dose of 77.9 Gy to the prostate, 64.6 Gy to the seminal vesicles, and 57 Gy to the pelvic lymph nodes. Patients were eligible if they had clinical stage T2b to T4, a Gleason sum score of 8 to 10, or a prostate- specific antigen level of 20ng/mL or greater. The primary endpoint of the study was evaluation of acute and late toxicities. Results: The median age was 69 years, with a median pretreatment prostate-specific antigen level of 12.5 ng/mL and Gleason score of 8. The pretreatment clinical stage was T1c in 4 patients, T2 in 11, and T3 in 3. All patients completed IMRT with median follow-up of 34 months (range, 28-40 months) The most common Grade 2 or higher toxicities were hypertension (61% of patients with Grade 2 and 11% with Grade 3), proteinuria (28% with Grade 2 and 6% with Grade 3), and leucopenia (28% with Grade 2). No Grade 4 or higher acute toxicities were reported. Late toxicities included proctitis (6% of patients with Grade 2 and 11% with Grade 3), rectal bleeding (6% with Grade 2 and 11% with Grade 3), hematuria (6% with Grade 2), proteinuria (17% with Grade 2), hyponatremia (6% with Grade 3), cystitis (6% with Grade 3), and urinary retention (6% with Grade 2 and 11% with Grade 3). Grade 4 prostatitis occurred in 1 patient (6%). Conclusions: Bevacizumab does not appear to exacerbate the acute effects of IMRT. Late toxicities may have been worsened with this regimen. Further investigations of bevacizumab with LTAS and IMRT should be

  8. Sensitization of Prostate Cancer Cells to Androgen Deprivation and Radiation via Manipulation of the MDM2 Pathway

    National Research Council Canada - National Science Library

    Pollack, Alan

    2004-01-01

    .... Our results indicate that MDM2 is central to prostate cancer response to AD, RT, and AD+RT. Our data establish that by reducing the expression of MDM2 with an antisense oligonucleotide (AS-MDM2...

  9. SLCO2B1 and SLCO1B3 as New Targets for Enhancing Androgen Deprivation Therapy for Prostate Cancer

    Science.gov (United States)

    2016-10-01

    Nutrition Examination Survey. Journal of clinical oncology : official journal of the American Society of Clinical Oncology...therapy for clinically localized prostate cancer. JAMA : the journal of the American Medical Association. Sep 16 1998;280(11):969-974. 12. Ross RW, Xie...evidence for prediagnostic use of statins in reducing risk of lethal prostate cancer. Journal of clinical oncology : official journal of the American

  10. Development of Novel Drugs That Target Coactivation Sites of the Androgen Receptor for Treatment of Antiandrogen-Resistant Prostate Cancer

    Science.gov (United States)

    2015-12-01

    Centre at the VGH 2660 Oak Street Vancouver, BC, Canada V6H 3Z6 REPORT DATE: December 2015 TYPE OF REPORT: Final PREPARED FOR: U.S. Army...Columbia AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBER Prostate Centre at the VGH 2660 Oak Street Vancouver, BC, Canada V6H 3Z6 9...relevance in prostate cancer (PCa) (2). Conventional AR-based therapeutics have mainly focused on targeting the traditional hormone binding pocket of

  11. Adipose Stem Cell-Based Therapeutic Targeting of Residual Androgens in African Americans with Bone-Metastatic Prostate Cancer

    Science.gov (United States)

    2015-11-01

    reduce or circumvent PC, especially among AA-men. 15. SUBJECT TERMS Prostate cancer, health disparity, stem cells, hormone inactivating enzymes, CRPC...aggressive CaP in AA patients [8, 9]. Family history accounts for 5-10% of total CaP cases [8, 9], and it does not differ among AA, Asian Americans...metastatic CaP [23]. Although initially effective, hormonal therapy is marked by progression to castration-resistant prostate cancer (CRPC) over a period of

  12. A Comparison Between Low-Dose-Rate Brachytherapy With or Without Androgen Deprivation, External Beam Radiation Therapy With or Without Androgen Deprivation, and Radical Prostatectomy With or Without Adjuvant or Salvage Radiation Therapy for High-Risk Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Ciezki, Jay P., E-mail: ciezkij@ccf.org [Taussig Cancer Institute, Department of Radiation Oncology, Cleveland Clinic, Cleveland, Ohio (United States); Weller, Michael; Reddy, Chandana A.; Kittel, Jeffrey; Singh, Harguneet; Tendulkar, Rahul; Stephans, Kevin L. [Taussig Cancer Institute, Department of Radiation Oncology, Cleveland Clinic, Cleveland, Ohio (United States); Ulchaker, James; Angermeier, Kenneth; Stephenson, Andrew; Campbell, Steven; Haber, Georges-Pascal; Klein, Eric A. [Glickman Urological and Kidney Institute, Department of Urology, Cleveland Clinic, Cleveland, Ohio (United States)

    2017-04-01

    Purpose: We compare the efficacy and toxicity among the 3 major modalities available used to treat high-risk prostate cancer (HRCaP). Methods and Materials: From 1996 to 2012, 2557 HRCaP patients were treated: 734 received external beam radiation therapy (EBRT) with or without androgen deprivation therapy (ADT), 515 received low-dose-rate prostate brachytherapy (LDR) with or without ADT, and 1308 received radical prostatectomy (RP) with or without EBRT. Biochemical relapse-free survival (bRFS), clinical relapse-free survival (cRFS), and prostate cancer–specific mortality (PCSM) were assessed. Toxicity was assessed using the Common Terminology Criteria for Adverse Events, version 4.03. The log-rank test compared bRFS and cRFS among the modalities, and Cox regression identified factors associated with bRFS and cRFS. Gray's test compared differences in late toxicity and PSCM among the modalities. Competing risk regression identified factors associated with PCSM. Results: The median follow-up time and age were 63.5 months and 65 years, respectively. The bRFS at 5 and 10 years, respectively, was 74% and 53% for EBRT, 74% and 52% for LDR, and 65% and 47% for RP (P=.0001). The cRFS at 5 and 10 years, respectively, was 85% and 73% for EBRT, 90% and 76% for LDR, and 89% and 75% for RP (P=.121). The PCSM at 5 and 10 years, respectively, was 5.3% and 11.2% for EBRT, 3.2% and 3.6% for LDR, and 2.8% and 6.8% for RP (P=.0004). The 10-year cumulative incidence of ≥grade 3 genitourinary toxicity was 8.1% for EBRT, 7.2% for LDR, and 16.4% for RP (P<.0001). The 10-year cumulative incidence of ≥grade 3 gastrointestinal toxicity was 4.6% for EBRT, 1.1% for LDR, and 1.0% for RP (P<.0001). Conclusion: HRCaP treated with EBRT, LDR, or RP yields efficacy showing better bRFS for LDR and EBRT relative to RP, equivalence for cRFS, and a PCSM advantage of LDR and RP over EBRT. The toxicity is lowest for LDR.

  13. A Comparison Between Low-Dose-Rate Brachytherapy With or Without Androgen Deprivation, External Beam Radiation Therapy With or Without Androgen Deprivation, and Radical Prostatectomy With or Without Adjuvant or Salvage Radiation Therapy for High-Risk Prostate Cancer.

    Science.gov (United States)

    Ciezki, Jay P; Weller, Michael; Reddy, Chandana A; Kittel, Jeffrey; Singh, Harguneet; Tendulkar, Rahul; Stephans, Kevin L; Ulchaker, James; Angermeier, Kenneth; Stephenson, Andrew; Campbell, Steven; Haber, Georges-Pascal; Klein, Eric A

    2017-04-01

    We compare the efficacy and toxicity among the 3 major modalities available used to treat high-risk prostate cancer (HRCaP). From 1996 to 2012, 2557 HRCaP patients were treated: 734 received external beam radiation therapy (EBRT) with or without androgen deprivation therapy (ADT), 515 received low-dose-rate prostate brachytherapy (LDR) with or without ADT, and 1308 received radical prostatectomy (RP) with or without EBRT. Biochemical relapse-free survival (bRFS), clinical relapse-free survival (cRFS), and prostate cancer-specific mortality (PCSM) were assessed. Toxicity was assessed using the Common Terminology Criteria for Adverse Events, version 4.03. The log-rank test compared bRFS and cRFS among the modalities, and Cox regression identified factors associated with bRFS and cRFS. Gray's test compared differences in late toxicity and PSCM among the modalities. Competing risk regression identified factors associated with PCSM. The median follow-up time and age were 63.5 months and 65 years, respectively. The bRFS at 5 and 10 years, respectively, was 74% and 53% for EBRT, 74% and 52% for LDR, and 65% and 47% for RP (P=.0001). The cRFS at 5 and 10 years, respectively, was 85% and 73% for EBRT, 90% and 76% for LDR, and 89% and 75% for RP (P=.121). The PCSM at 5 and 10 years, respectively, was 5.3% and 11.2% for EBRT, 3.2% and 3.6% for LDR, and 2.8% and 6.8% for RP (P=.0004). The 10-year cumulative incidence of ≥grade 3 genitourinary toxicity was 8.1% for EBRT, 7.2% for LDR, and 16.4% for RP (P<.0001). The 10-year cumulative incidence of ≥grade 3 gastrointestinal toxicity was 4.6% for EBRT, 1.1% for LDR, and 1.0% for RP (P<.0001). HRCaP treated with EBRT, LDR, or RP yields efficacy showing better bRFS for LDR and EBRT relative to RP, equivalence for cRFS, and a PCSM advantage of LDR and RP over EBRT. The toxicity is lowest for LDR. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Effect of Saw Palmetto Supplements on Androgen-Sensitive LNCaP Human Prostate Cancer Cell Number and Syrian Hamster Flank Organ Growth

    Directory of Open Access Journals (Sweden)

    Alexander B. Opoku-Acheampong

    2016-01-01

    Full Text Available Saw palmetto supplements (SPS are commonly consumed by men with prostate cancer. We investigated whether SPS fatty acids and phytosterols concentrations determine their growth-inhibitory action in androgen-sensitive LNCaP cells and hamster flank organs. High long-chain fatty acids-low phytosterols (HLLP SPS ≥ 750 nM with testosterone significantly increased and ≥500 nM with dihydrotestosterone significantly decreased LNCaP cell number. High long-chain fatty acids-high phytosterols (HLHP SPS ≥ 500 nM with dihydrotestosterone and high medium-chain fatty acids-low phytosterols (HMLP SPS ≥ 750 nM or with androgens significantly decreased LNCaP cell number (n=3; p<0.05. Five- to six-week-old, castrated male Syrian hamsters were randomized to control (n=4, HLLP, HLHP, and HMLP SPS (n=6 groups. Testosterone or dihydrotestosterone was applied topically daily for 21 days to the right flank organ; the left flank organ was treated with ethanol and served as the control. Thirty minutes later, SPS or ethanol was applied to each flank organ in treatment and control groups, respectively. SPS treatments caused a notable but nonsignificant reduction in the difference between left and right flank organ growth in testosterone-treated SPS groups compared to the control. The same level of inhibition was not seen in dihydrotestosterone-treated SPS groups (p<0.05. Results may suggest that SPS inhibit 5α-reductase thereby preventing hamster flank organ growth.

  15. PUMA decreases the growth of prostate cancer PC-3 cells independent of p53.

    Science.gov (United States)

    Shan, Zhengfei; Liu, Qingzuo; Li, Yuling; Wu, Jitao; Sun, Dekang; Gao, Zhenli

    2017-03-01

    PUMA (p53 upregulated modulator of apoptosis), a member of the B-cell lymphoma 2 (Bcl-2) protein family, is a pro-apoptotic protein. PUMA expression is modulated by the tumor suppressor p53. PUMA has a role in rapid cell death via p53-dependent and -independent mechanisms. To evaluate whether p53 is required for PUMA-mediated apoptosis in prostate cancer cells, p53 protein was silenced in human prostate cancer PC-3 cells by using p53 small interfering RNA (siRNA). The interference efficiency of p53 on RNA and protein levels was detected by reverse transcription-quantitative polymerase chain reaction and western blotting. Cell proliferation and p21 expression were subsequently examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and western blot analysis, respectively. p53-silenced or control PC-3 cells were transfected with pCEP4-(hemagglutinin)-PUMA plasmid, or non-carrier plasmid. Enzyme-linked immunosorbent assay was used to determine cell apoptosis by measuring histone release and caspase-3 activation, and MTT assay was used to measure cell viability. In addition, the expression of pro-apoptosis protein Bax and anti-apoptosis protein Bcl-2 were evaluated. The results of the present study revealed that p53 siRNA significantly suppressed p53 RNA and protein expression in PC-3 cells. Deficiency of p53 increased the cell growth rate and decreased p21 expression. However, PUMA overexpression remained able to induce apoptosis in p53-silenced and control cells by increasing Bax expression and decreasing Bcl-2 expression, leading to the activation of caspase-3. These results suggest that PUMA may mediate apoptosis of prostate cancer PC-3 cells, potentially independently of p53. Furthermore, PUMA gene treatment to induce cancer cell apoptosis may be more efficient compared with p53-dependent apoptosis, where loss of p53 expression or function may lead to limited efficacy of PUMA expression. Therefore, the present study proposes the

  16. Independent association between time to prostate-specific antigen (PSA) nadir and PSA progression-free survival in patients with docetaxel-naïve, metastatic castration-resistant prostate cancer receiving abiraterone acetate, but not enzalutamide.

    Science.gov (United States)

    Miyake, Hideaki; Hara, Takuto; Tamura, Keita; Sugiyama, Takayuki; Furuse, Hiroshi; Ozono, Seiichiro; Fujisawa, Masato

    2017-06-01

    The objective of this study was to compare the prognostic effect of time to prostate-specific antigen (PSA) nadir (TTPN) after treatment with abiraterone acetate (AA) and enzalutamide (Enz) in patients with docetaxel-naïve, metastatic castration-resistant prostate cancer (mCRPC). This study included a total of 297 consecutive patients with mCRPC, of whom 125 and 172 received AA and Enz, respectively, without previous treatment with docetaxel and subsequently achieved any degree of PSA reduction after the administration of either agent. The mean values of TTPN in the AA and Enz groups were 19 and 14 weeks, respectively. Despite the lack of significant differences in several parameters according to the mean TTPN in the Enz group, patients with TTPN>19 weeks were characterized by longer duration of androgen deprivation therapy, better performance status, lower incidence of bone metastasis, lower value of nadir PSA, and higher incidence of PSA response than those with TTPN ≤19 weeks in the AA group. The PSA progression-free survival (PFS) in patients with TTPN >19 weeks was significantly superior when compared with TTPN ≤19 weeks in the AA group; however, there was no significant effect of the mean TTPN on the PSA-PFS in the Enz group. Furthermore, TTPN was identified as one of the independent predictors of PSA-PFS in the AA group but not in Enz group. A longer time to reach a PSA nadir after treatment with AA, but not Enz, appeared to be associated with favorable disease control in patients with docetaxel-naïve mCRPC. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. A phase II RCT and economic analysis of three exercise delivery methods in men with prostate cancer on androgen deprivation therapy.

    Science.gov (United States)

    Alibhai, Shabbir M H; Santa Mina, Daniel; Ritvo, Paul; Sabiston, Catherine; Krahn, Murray; Tomlinson, George; Matthew, Andrew; Segal, Roanne; Warde, Padraig; Durbano, Sara; O'Neill, Meagan; Culos-Reed, Nicole

    2015-04-25

    Androgen deprivation therapy is commonly used to treat prostate cancer, the most common visceral cancer in men. However, various side effects often worsen physical functioning and reduce well-being among men on this treatment. Based on existing evidence, both resistance and aerobic training provide benefits for this population yet adherence rates are often low. The method of exercise delivery (supervised in-center or home-based) may be important, yet few studies have compared different models. Additionally, long-term exercise adherence is critical to achieve sustained