Update on options for treatment of metastatic castration-resistant prostate cancer

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Prakash Vishnu

2010-03-01

Full Text Available Prakash Vishnu, Winston W TanDivision of Hematology Oncology, Mayo Clinic, Jacksonville, FL, USABackground: Prostate cancer is one of the most common cancers in men in US and European countries. Despite having a favorable prognosis, the incidence of incurable metastatic disease and mortality in the US is about 28,000 per year. Although hormone-based androgen deprivation therapies typically result in rapid responses, nearly all patients eventually develop progressive castration-resistant disease state. With readily available prostate-specific antigen (PSA testing, most of these patients are asymptomatic and manifest progression simply as a rising PSA. In patients with castration-resistant prostate cancer (CRPC, the median survival is about 1–2 years, with improvements in survival seen mostly with docetaxel-based regimens. The purpose of this article is to review the recent developments in the treatment of advanced CRPC.Recent findings: Since the two landmark trials (TAX-327 and Southwest Oncology Group 99–16 in CRPC, several newer cytotoxic drugs (epothilones, satraplatin, targeted agents (abiraterone, MDV3100 and vaccines have been tested in phase II and III setting with promising results.Conclusions: The role of newer agents in the treatment of CRPC still needs to be validated by phase III trials, which are currently ongoing. Whilst the novel biomarkers, ‘circulating tumor cells’, have been shown to provide important prognostic information and are anticipated to be incorporated in future clinical decision-making, their exact utility and relevance calls for a larger prospective validation.Keywords: castration-resistant prostate cancer, novel therapies, mechanisms of resistance, circulating tumor cells

PTEN loss promotes intratumoral androgen synthesis and tumor microenvironment remodeling via aberrant activation of RUNX2 in castration-resistant prostate cancer

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Yang, Yinhui; Bai, Yang; He, Yundong; Zhao, Yu; Chen, Jiaxiang; Ma, Linlin; Pan, Yunqian; Hinten, Michael; Zhang, Jun; Karnes, R. Jeffrey; Kohli, Manish; Westendorf, Jennifer J.; Li, Benyi; Zhu, Runzhi; Huang, Haojie; Xu, Wanhai

2018-01-01

Purpose Intratumoral androgen synthesis (IAS) is a key mechanism promoting androgen receptor (AR)reactivation and anti-androgen resistance in castration-resistant prostate cancer (CRPC). However, signaling pathways driving aberrant IAS remain poorly understood. Experimental Design The effect of components of the AKT-RUNX2-osteocalcin (OCN)-GPRC6A-CREB signaling axis on expression of steroidogenesis genes CYP11A1 and CYP17A1 and testosterone level were examined in PTEN-null human PCa cell lines. Pten knockout mice were employed to examine the effect of Runx2 heterozygous deletion or abiraterone acetate (ABA), a prodrug of the CYP17A1 inhibitor abiraterone on Cyp11a1 and Cyp17a1 expression, testosterone level and tumor microenvironment (TME) remodeling in vivo. Results We uncovered that activation of the AKT-RUNX2-OCN-GPRC6A-CREB signaling axis induced expression of CYP11A1 and CYP17A1 and testosterone production in PTEN-null PCa cell lines in culture. Deletion of Runx2 in Pten homozygous knockout prostate tumors decreased Cyp11a1 and Cyp17a1 expression, testosterone level and tumor growth in castrated mice. ABA treatment also inhibited testosterone synthesis and alleviated Pten loss-induced tumorigenesis in vivo. Pten deletion induced TME remodeling, but Runx2 heterozygous deletion or ABA treatment reversed the effect of Pten loss by decreasing expression of the collagenase Mmp9. Conclusions Abnormal RUNX2 activation plays a pivotal role in PTEN loss-induced IAS and TME remodeling, suggesting that the identified signaling cascade represents a viable target for effective treatment of PTEN-null PCa including CRPC. PMID:29167276

FOXA1 promotes tumor progression in prostate cancer and represents a novel hallmark of castration-resistant prostate cancer.

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Gerhardt, Josefine; Montani, Matteo; Wild, Peter; Beer, Marc; Huber, Fabian; Hermanns, Thomas; Müntener, Michael; Kristiansen, Glen

2012-02-01

Forkhead box protein A1 (FOXA1) modulates the transactivation of steroid hormone receptors and thus may influence tumor growth and hormone responsiveness in prostate cancer. We therefore investigated the correlation of FOXA1 expression with clinical parameters, prostate-specific antigen (PSA) relapse-free survival, and hormone receptor expression in a large cohort of prostate cancer patients at different disease stages. FOXA1 expression did not differ significantly between benign glands from the peripheral zone and primary peripheral zone prostate carcinomas. However, FOXA1 was overexpressed in metastases and particularly in castration-resistant cases, but was expressed at lower levels in both normal and neoplastic transitional zone tissues. FOXA1 levels correlated with higher pT stages and Gleason scores, as well as with androgen (AR) and estrogen receptor expression. Moreover, FOXA1 overexpression was associated with faster biochemical disease progression, which was pronounced in patients with low AR levels. Finally, siRNA-based knockdown of FOXA1 induced decreased cell proliferation and migration. Moreover, in vitro tumorigenicity was inducible by ARs only in the presence of FOXA1, substantiating a functional cooperation between FOXA1 and AR. In conclusion, FOXA1 expression is associated with tumor progression, dedifferentiation of prostate cancer cells, and poorer prognosis, as well as with cellular proliferation and migration and with AR signaling. These findings suggest FOXA1 overexpression as a novel mechanism inducing castration resistance in prostate cancer. Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Castration resistant prostate cancer - something new in the year 2014?

International Nuclear Information System (INIS)

Marencak, J.

2014-01-01

Prostate cancer (PC) is the most frequent solid neoplasm in Europe and therefore is regarded as one of the major medical problem of the male population. PC is extremely complicated and interindividual different tumor. The method of treatment depends on several factors, but mainly on the stage of prostate cancer. The term Hormone resistant (refractory) prostate cancer (HRPC) was used in older terminology. HRPC is cancer that progresses despite castrate levels of testosterone achieved androgen deprivation therapy (ADT), which is resistant to any hormonal therapy. Currently is increasingly used (instead of name HRPC) name CRPC – so called PC resistant for castration (CRPC – castration resistant prostate cancer), which is still able to respond to certain hormonal manipulation, although it meets the the criteria for HRPC. This state probably arises from either clonal selection of androgen – independent cell lines or increased ligand – independent activation of androgen receptors. Men with CRPC are quite a heterogeneous group; they include men with increasing prostate specific antigen (PSA) only and no demonstrable metastases, and men who have many bone and/ or visceral metastases, pain and poor functional status. Survival can range from only a few months to 4 years or more. Historically, therapy had little effect beyond modest palliation. More recently, significantly more options have become available and there are now several treatments that not only improve quality of life and pain palliation, but also increase overall survival. Some of the trials with important results for the treatment of CRPC are summarized in this paper. Objectives of article: provide information to the general medical community (and especially urologists and oncologists) about the possible pathogenesis of CRPC, complicated issues of treatment and evaluation of its effectiveness in patients with CRPC. The article presented basic data on the current and future possibilities of such therapy

Metalloproteinase 11, potential marker and molecular target in advanced and castration-resistant prostate cancer. Culture study of peritumoral fibroblasts.

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Fernandez-Gomez, J M; Eiro, N; García-Rodríguez, J J; Quintás-Blanco, A; Gonzalez-Ruiz de León, C; Perez de Haro, M L; Vizoso-Piñero, F

To analyze the expression of metalloprotein 11 (MMP11) in cultured fibroblasts obtained from human prostate tumors with different clinical and pathological characteristics. For this study we analyzed samples of transrectal prostate biopsies from tumors with different characteristics, treated with or whithout androgen deprivation (AD). After optimization of the culture method, fibroblasts were isolated and cultured to perform the study (PCR) of MMP11 mRNA. Finally, 37 cases were studied: 5 samples of benign prostatic hyperplasia, 14 cases with localized neoplasms (7 high-risk according to the D'Amico classification), 5 with metastasic tumors (bone metastases), and 13 treated with AD therapy, of which 6 fulfilled the requirements to be defined as resistant to castration. In tumors without AD therapy, MMP11 expression was significantly higher (P=.001) in fibroblasts of higher grade tumors. A significant (P=.001) correlation was found between PSA and expression of MMP11 in fibroblast s and a significant increase of MMP11 expression in metastatic tumors. In tumors with AD therapy, a significantly greater expression of MMP11 was observed in resistant to castration patients than in those sensitive to castration (P=.003). In advanced prostate tumors or in stages of increased tumor aggressiveness, the production of MMP11 by fibroblasts is significantly greater than in non-metastatic tumors or in AD sensitive tumors. Copyright © 2016 AEU. Publicado por Elsevier España, S.L.U. All rights reserved.

Metastatic castration-resistant prostate cancer: a current view on drug therapy and alternative tumor cell regulation

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R. A. Gafanov

2018-01-01

Full Text Available Prostate cancer (PC is one of the most common causes of death from malignant neoplasms in men in many countries around the world. Transmission of the signal in the androgenic axis of regulation is crucial for the development and progression of PC. Despite the constant dependence on androgen receptor signals in castration resistance, the use of new anti-androgenic drugs invariably leads to the stability  of the ongoing treatment. The interaction of androgen receptor and alternative (phosphoinositide-3-kinases, PI3K pathways in the regulation of cells can be one of the mechanisms of resistance to treatment. In this article, we describe current treatments for metastatic castration-resistant PC and the possible role of the PI3K pathway in the pathogenesis and progression of PC.

Super-Penetrant Androgen Receptor: Overcoming Enzalutamide Sensitivity in Castration-Resistant Prostate Cancer

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2016-07-01

Prostate Cancer Research Symposium- Prostate Cancer Epigenetic Reprogramming of the Androgen Receptor in Castration Resistant Prostate Cancer , May19... cancer cells rely critically on the androgen receptor (AR) for initiation, growth and progression to castration resistant prostate cancer (CRPC...Androgen receptor, castration resistant prostate cancer , Enzalutamide , kinases. 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER

Cholesterol biosynthesis inhibitor RO 48-8071 suppresses growth of hormone-dependent and castration-resistant prostate cancer cells

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Liang Y

2016-05-01

Full Text Available Yayun Liang,1 Benford Mafuvadze,1 Johannes D Aebi,2 Salman M Hyder1 1Dalton Cardiovascular Research Center and Department of Biomedical Sciences, University of Missouri-Columbia, Columbia, MO, USA; 2Medicinal Chemistry, Roche Pharma Research and Early Development (pRED, Roche Innovation Center Basel, F Hoffmann-La Roche Ltd., Basel, Switzerland Abstract: Standard treatment for primary prostate cancer includes systemic exposure to chemotherapeutic drugs that target androgen receptor or antihormone therapy (chemical castration; however, drug-resistant cancer cells generally emerge during treatment, limiting the continued use of systemic chemotherapy. Patients are then treated with more toxic standard therapies. Therefore, there is an urgent need for novel and more effective treatments for prostate cancer. The cholesterol biosynthetic pathway is an attractive therapeutic target for treating endocrine-dependent cancers because cholesterol is an essential structural and functional component of cell membranes as well as the metabolic precursor of endogenous steroid hormones. In this study, we have examined the effects of RO 48-8071 (4'-[6-(allylmethylaminohexyloxy]-4-bromo-2'-fluorobenzophenone fumarate; Roche Pharmaceuticals internal reference: RO0488071 (RO, which is an inhibitor of 2, 3-oxidosqualene cyclase (a key enzyme in the cholesterol biosynthetic pathway, on prostate cancer cells. Exposure of both hormone-dependent and castration-resistant human prostate cancer cells to RO reduced prostate cancer cell viability and induced apoptosis in vitro. RO treatment reduced androgen receptor protein expression in hormone-dependent prostate cancer cells and increased estrogen receptor β (ERβ protein expression in both hormone-dependent and castration-resistant prostate cancer cell lines. Combining RO with an ERβ agonist increased its ability to reduce castration-resistant prostate cancer cell viability. In addition, RO effectively suppressed the

ASC-J9 Suppresses Castration-Resistant Prostate Cancer Growth through Degradation of Full-length and Splice Variant Androgen Receptors

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Shinichi Yamashita

2012-01-01

Full Text Available Early studies suggested androgen receptor (AR splice variants might contribute to the progression of prostate cancer (PCa into castration resistance. However, the therapeutic strategy to target these AR splice variants still remains unresolved. Through tissue survey of tumors from the same patients before and after castration resistance, we found that the expression of AR3, a major AR splice variant that lacks the AR ligand-binding domain, was substantially increased after castration resistance development. The currently used antiandrogen, Casodex, showed little growth suppression in CWR22Rv1 cells. Importantly, we found that AR degradation enhancer ASC-J9 could degrade both full-length (fAR and AR3 in CWR22Rv1 cells as well as in C4-2 and C81 cells with addition of AR3. The consequences of such degradation of both fAR and AR3 might then result in the inhibition of AR transcriptional activity and cell growth in vitro. More importantly, suppression of AR3 specifically by short-hairpin AR3 or degradation of AR3 by ASC-J9 resulted in suppression of AR transcriptional activity and cell growth in CWR22Rv1-fARKD (fAR knockdown cells in which DHT failed to induce, suggesting the importance of targeting AR3. Finally, we demonstrated the in vivo therapeutic effects of ASC-J9 by showing the inhibition of PCa growth using the xenografted model of CWR22Rv1 cells orthotopically implanted into castrated nude mice with undetectable serum testosterone. These results suggested that targeting both fAR- and AR3-mediated PCa growth by ASC-J9 may represent the novel therapeutic approach to suppress castration-resistant PCa. Successful clinical trials targeting both fAR and AR3 may help us to battle castration-resistant PCa in the future.

Androgen receptor expression in Circulating Tumor Cells from castration-resistant prostate cancer patients with novel endocrine agents

NARCIS (Netherlands)

Crespo, M.; van Dalum, Guus; Ferraldeschi, R.; Zafeiriou, Z.; Sideris, S.; Lorente, D.; Bianchini, D.; Rodrigues, D.N.; Rijsnaes, R.; Miranda, S.; Figueiredo, I.; Flohr, P.; Nowakowska, K.; de Bono, J.S.; Terstappen, Leonardus Wendelinus Mathias Marie; Attard, G.

2015-01-01

Background: Abiraterone and enzalutamide are novel endocrine treatments that abrogate androgen receptor (AR) signalling in castration-resistant prostate cancer (CRPC). Here, we developed a circulating tumour cells (CTCs)-based assay to evaluate AR expression in real-time in CRPC and investigated

A gain-of-function mutation in DHT synthesis in castration-resistant prostate cancer.

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Chang, Kai-Hsiung; Li, Rui; Kuri, Barbara; Lotan, Yair; Roehrborn, Claus G; Liu, Jiayan; Vessella, Robert; Nelson, Peter S; Kapur, Payal; Guo, Xiaofeng; Mirzaei, Hamid; Auchus, Richard J; Sharifi, Nima

2013-08-29

Growth of prostate cancer cells is dependent upon androgen stimulation of the androgen receptor (AR). Dihydrotestosterone (DHT), the most potent androgen, is usually synthesized in the prostate from testosterone secreted by the testis. Following chemical or surgical castration, prostate cancers usually shrink owing to testosterone deprivation. However, tumors often recur, forming castration-resistant prostate cancer (CRPC). Here, we show that CRPC sometimes expresses a gain-of-stability mutation that leads to a gain-of-function in 3β-hydroxysteroid dehydrogenase type 1 (3βHSD1), which catalyzes the initial rate-limiting step in conversion of the adrenal-derived steroid dehydroepiandrosterone to DHT. The mutation (N367T) does not affect catalytic function, but it renders the enzyme resistant to ubiquitination and degradation, leading to profound accumulation. Whereas dehydroepiandrosterone conversion to DHT is usually very limited, expression of 367T accelerates this conversion and provides the DHT necessary to activate the AR. We suggest that 3βHSD1 is a valid target for the treatment of CRPC. Copyright © 2013 Elsevier Inc. All rights reserved.

Androgens as therapy for androgen receptor-positive castration-resistant prostate cancer

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Lin Hui-Ping

2011-08-01

Full Text Available Abstract Prostate cancer is the most frequently diagnosed non-cutaneous tumor of men in Western countries. While surgery is often successful for organ-confined prostate cancer, androgen ablation therapy is the primary treatment for metastatic prostate cancer. However, this therapy is associated with several undesired side-effects, including increased risk of cardiovascular diseases. Shortening the period of androgen ablation therapy may benefit prostate cancer patients. Intermittent Androgen Deprivation therapy improves quality of life, reduces toxicity and medical costs, and delays disease progression in some patients. Cell culture and xenograft studies using androgen receptor (AR-positive castration-resistant human prostate cancers cells (LNCaP, ARCaP, and PC-3 cells over-expressing AR suggest that androgens may suppress the growth of AR-rich prostate cancer cells. Androgens cause growth inhibition and G1 cell cycle arrest in these cells by regulating c-Myc, Skp2, and p27Kip via AR. Higher dosages of testosterone cause greater growth inhibition of relapsed tumors. Manipulating androgen/AR signaling may therefore be a potential therapy for AR-positive advanced prostate cancer.

Evaluation of Tumor Viability for Primary and Bone Metastases in Metastatic Castration-Resistant Prostate Cancer Using Whole-Body Magnetic Resonance Imaging

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Hiromichi Iwamura

2018-01-01

Full Text Available In contrast to bone scan and computed tomography (CT, which depend on osteoblastic response to detect bone metastasis, whole-body magnetic resonance imaging (WB-MRI may be able to directly detect viable tumors. A 75-year-old male who had progressive metastatic prostate cancer during primary androgen deprivation therapy was referred to our hospital. Although bone scan and CT showed multiple bone metastases, WB-MRI suggested nonviable bone metastasis and viable tumor of the primary lesion. Prostate needle biopsy demonstrated viable prostate cancer cells from 10 of 12 cores. In contrast, CT-guided needle biopsy from bone metastasis of the lumbar vertebra revealed no malignant cells. Based on these findings, we reasoned that viable tumor cells inducing disease progression may primarily exist in the primary lesions and not in the metastatic lesions, and combined prostate radiotherapy and systemic hormonal therapy resulted in successful clinical response and disease control. The use of WB-MRI to detect viable disease lesions may enable us to design optimal treatment strategies for patients with metastatic castration-resistant prostate cancer.

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

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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.

Metastatic castration-resistant prostate cancer: time for innovation.

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Tucci, Marcello; Scagliotti, Giorgio Vittorio; Vignani, Francesca

2015-01-01

Androgen deprivation is the mainstay of advanced prostate cancer treatment. Despite initial responses, almost all patients progress to castration-resistant prostate cancer (CRPC). The understanding of the biology of CRPC and the evidence that CRPC still remains driven by androgen receptor signaling led to the discovery of new therapeutic targets. In the last few years, large Phase III trials showed improvements in survival and outcomes and led to the approval of a CYP17 inhibitor (abiraterone), an androgen receptor antagonist (enzalutamide), the taxane cabazitaxel, an α-emitter (radium-223), the bone resorption-targeting drug denosumab and an immunotherapy (sipuleucel-T). This article describes the molecular mechanisms underlying castration resistance, discusses recent and ongoing trials and offers some insights into identifying the best sequence of new drugs.

Longitudinal tracking of subpopulation dynamics and molecular changes during LNCaP cell castration and identification of inhibitors that could target the PSA−/lo castration-resistant cells

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Rycaj, Kiera; Cho, Eun Jeong; Liu, Xin; Chao, Hsueh-Ping; Liu, Bigang; Li, Qiuhui; Devkota, Ashwini K.; Zhang, Dingxiao; Chen, Xin; Moore, John; Dalby, Kevin N.; Tang, Dean G.

2016-01-01

We have recently demonstrated that the undifferentiated PSA−/lo prostate cancer (PCa) cell population harbors self-renewing long-term tumor-propagating cells that are refractory to castration, thus representing a therapeutic target. Our goals here are, by using the same lineage-tracing reporter system, to track the dynamic changes of PSA−/lo and PSA+ cells upon castration in vitro, investigate the molecular changes accompanying persistent castration, and develop large numbers of PSA−/lo PCa cells for drug screening. To these ends, we treated LNCaP cells infected with the PSAP-GFP reporter with three regimens of castration, i.e., CDSS, CDSS plus bicalutamide, and MDV3100 continuously for up to ~21 months. We observed that in the first ~7 months, castration led to time-dependent increases in PSA−/lo cells, loss of AR and PSA expression, increased expression of cancer stem cell markers, and many other molecular changes. Meanwhile, castrated LNCaP cells became resistant to high concentrations of MDV3100, chemotherapeutic drugs, and other agents. However, targeted and medium-throughput library screening identified several kinase (e.g., IGF-1R, AKT, PI3K/mTOR, Syk, GSK3) inhibitors as well as the BCL2 inhibitor that could effectively sensitize the LNCaP-CRPC cells to killing. Of interest, LNCaP cells castrated for >7 months showed evidence of cyclic changes in AR and the mTOR/AKT signaling pathways potentially involving epigenetic mechanisms. These observations indicate that castration elicits numerous molecular changes and leads to enrichment of PSA−/lo PCa cells. The ability to generate large numbers of PSA−/lo PCa cells should allow future high-throughput screening to identify novel therapeutics that specifically target this population. PMID:26871947

Pharmacodynamic study of the oral hedgehog pathway inhibitor, vismodegib, in patients with metastatic castration-resistant prostate cancer.

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Maughan, Benjamin L; Suzman, Daniel L; Luber, Brandon; Wang, Hao; Glavaris, Stephanie; Hughes, Robert; Sullivan, Rana; Harb, Rana; Boudadi, Karim; Paller, Channing; Eisenberger, Mario; Demarzo, Angelo; Ross, Ashely; Antonarakis, Emmanuel S

2016-12-01

Hedgehog (Hh) pathway signaling has been implicated in prostate cancer tumorigenesis and metastatic development and may be upregulated even further in the castration-resistant state. We hypothesized that antagonism of the Hh pathway with vismodegib in men with metastatic castration-resistant prostate cancer (mCRPC) would result in pathway engagement, inhibition and perhaps induce measurable clinical responses in patients. This is a single-arm study of oral daily vismodegib in men with mCRPC. All patients were required to have biopsies of the tumor and skin (a surrogate tissue) at baseline and after 4 weeks of therapy. Ten patients were planned for enrollment. The primary outcome was the pharmacodynamic assessment of Gli1 mRNA suppression with vismodegib in tumor tissue. Secondary outcomes included PSA response rates, progression-free survival (PFS), overall survival (OS) and safety. Nine patients were enrolled. Gli1 mRNA was significantly suppressed by vismodegib in both tumor tissue (4/7 evaluable biopsies, 57%) and benign skin biopsies (6/8 evaluable biopsies, 75%). The median number of treatment cycles completed was three, with a median PFS of 1.9 months (95% CI 1.3, NA), and a median OS of 7.04 months (95% CI 3.4, NA). No patient achieved a PSA reduction or a measurable tumor response. Safety data were consistent with the known toxicities of vismodegib. Hh signaling, as measured by Gli1 mRNA expression in mCRPC tissues, was suppressed with vismodegib in the majority of patients. Despite this pharmacodynamic response that indicated target inhibition in some patients, there was no apparent signal of clinical activity. Vismodegib will not be developed further as monotherapy in mCRPC.

YAP1 regulates prostate cancer stem cell-like characteristics to promote castration resistant growth

DEFF Research Database (Denmark)

Jiang, Ning; Ke, Binghu; Hjort-Jensen, Kim

2017-01-01

Castration resistant prostate cancer (CRPC) is a stage of relapse that arises after various forms of androgen ablation therapy (ADT) and causes significant morbidity and mortality. However, the mechanism underlying progression to CRPC remains poorly understood. Here, we report that YAP1, which...... is negatively regulated by AR, influences prostate cancer (PCa) cell self-renewal and CRPC development. Specifically, we found that AR directly regulates the methylation of YAP1 gene promoter via the formation of a complex with Polycomb group protein EZH2 and DNMT3a. In normal conditions, AR recruits EZH2......-differentiation of PCa cells to stem/progenitor-like cells (PCSC), which potentially contribute to disease recurrence. Finally, the knock down of YAP1 expression or the inhibition of YAP1 function by Verteporfin in TRAMP prostate cancer mice significantly suppresses tumor recurrence following castration. In conclusion...

Update on options for treatment of metastatic castration-resistant prostate cancer.

Science.gov (United States)

Vishnu, Prakash; Tan, Winston W

2010-06-24

Prostate cancer is one of the most common cancers in men in US and European countries. Despite having a favorable prognosis, the incidence of incurable metastatic disease and mortality in the US is about 28,000 per year. Although hormone-based androgen deprivation therapies typically result in rapid responses, nearly all patients eventually develop progressive castration-resistant disease state. With readily available prostate-specific antigen (PSA) testing, most of these patients are asymptomatic and manifest progression simply as a rising PSA. In patients with castration-resistant prostate cancer (CRPC), the median survival is about 1-2 years, with improvements in survival seen mostly with docetaxel-based regimens. The purpose of this article is to review the recent developments in the treatment of advanced CRPC. Since the two landmark trials (TAX-327 and Southwest Oncology Group 99-16) in CRPC, several newer cytotoxic drugs (epothilones, satraplatin), targeted agents (abiraterone, MDV3100) and vaccines have been tested in phase II and III setting with promising results. The role of newer agents in the treatment of CRPC still needs to be validated by phase III trials, which are currently ongoing. Whilst the novel biomarkers, 'circulating tumor cells', have been shown to provide important prognostic information and are anticipated to be incorporated in future clinical decision-making, their exact utility and relevance calls for a larger prospective validation.

New possibilities and view for treatment of castration resistant prostate cancer

International Nuclear Information System (INIS)

Barilla, R.; Andrasina, I.

2012-01-01

Prostate cancer is currently known as the most common cancer and the second leading cause of death from cancer in men in Western population. Advanced prostate cancer is initially sensitive to androgen-deprivation therapy (ADT) but later on progresses to castration resistant state. Understanding the mechanisms that transform prostate cancer (PCA) into a castration-resistant state enables investigators to explore suppression of extraresticular andronegs and other critical pathways to suggest appropriate and rational therapeutic design. Docetaxel based chemotherapy is established as the standard first line chemotherapy in patients with metastatic castration-resistant advanced prostate cancer with improved survival. However, prognosis remains poor and median survival is usually not longer than 2 years. Several Phase III studies have been completed recently, e.g. with new antiandrogens, new taxanes, immunotherapy and therapeutic antibodies. Multidisciplinary management and optimization of their role and and the most appropriate timing is the most important task in the treatment of advanced prostate cancer. (author)

Sortilin regulates progranulin action in castration-resistant prostate cancer cells.

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Tanimoto, Ryuta; Morcavallo, Alaide; Terracciano, Mario; Xu, Shi-Qiong; Stefanello, Manuela; Buraschi, Simone; Lu, Kuojung G; Bagley, Demetrius H; Gomella, Leonard G; Scotlandi, Katia; Belfiore, Antonino; Iozzo, Renato V; Morrione, Andrea

2015-01-01

The growth factor progranulin is as an important regulator of transformation in several cellular systems. We have previously demonstrated that progranulin acts as an autocrine growth factor and stimulates motility, proliferation, and anchorage-independent growth of castration-resistant prostate cancer cells, supporting the hypothesis that progranulin may play a critical role in prostate cancer progression. However, the mechanisms regulating progranulin action in castration-resistant prostate cancer cells have not been characterized. Sortilin, a single-pass type I transmembrane protein of the vacuolar protein sorting 10 family, binds progranulin in neurons and negatively regulates progranulin signaling by mediating progranulin targeting for lysosomal degradation. However, whether sortilin is expressed in prostate cancer cells and plays any role in regulating progranulin action has not been established. Here, we show that sortilin is expressed at very low levels in castration-resistant PC3 and DU145 cells. Significantly, enhancing sortilin expression in PC3 and DU145 cells severely diminishes progranulin levels and inhibits motility, invasion, proliferation, and anchorage-independent growth. In addition, sortilin overexpression negatively modulates Akt (protein kinase B, PKB) stability. These results are recapitulated by depleting endogenous progranulin in PC3 and DU145 cells. On the contrary, targeting sortilin by short hairpin RNA approaches enhances progranulin levels and promotes motility, invasion, and anchorage-independent growth. We dissected the mechanisms of sortilin action and demonstrated that sortilin promotes progranulin endocytosis through a clathrin-dependent pathway, sorting into early endosomes and subsequent lysosomal degradation. Collectively, these results point out a critical role for sortilin in regulating progranulin action in castration-resistant prostate cancer cells, suggesting that sortilin loss may contribute to prostate cancer progression.

Estradiol suppresses tissue androgens and prostate cancer growth in castration resistant prostate cancer

International Nuclear Information System (INIS)

Montgomery, Bruce; Nelson, Peter S; Vessella, Robert; Kalhorn, Tom; Hess, David; Corey, Eva

2010-01-01

Estrogens suppress tumor growth in prostate cancer which progresses despite anorchid serum androgen levels, termed castration resistant prostate cancers (CRPC), although the mechanisms are unclear. We hypothesize that estrogen inhibits CRPC in anorchid animals by suppressing tumoral androgens, an effect independent of the estrogen receptor. The human CRPC xenograft LuCaP 35V was implanted into orchiectomized male SCID mice and established tumors were treated with placebo, 17β-estradiol or 17β-estradiol and estrogen receptor antagonist ICI 182,780. Effects of 17β-estradiol on tumor growth were evaluated and tissue testosterone (T) and dihydrotestosterone (DHT) evaluated by mass spectrometry. Treatment of LuCaP 35V with 17β-estradiol slowed tumor growth compared to controls (tumor volume at day 21: 785 ± 81 mm 3 vs. 1195 ± 84 mm 3 , p = 0.002). Survival was also significantly improved in animals treated with 17β-estradiol (p = 0.03). The addition of the estrogen receptor antagonist ICI 182,780 did not significantly change survival or growth. 17β-estradiol in the presence and absence of ICI 182,780 suppressed tumor testosterone (T) and dihydrotestosterone (DHT) as assayed by mass spectrometry. Tissue androgens in placebo treated LuCaP 35V xenografts were; T = 0.71 ± 0.28 pg/mg and DHT = 1.73 ± 0.36 pg/mg. In 17β-estradiol treated LuCaP35V xenografts the tissue androgens were, T = 0.20 ± 0.10 pg/mg and DHT = 0.15 ± 0.15 pg/mg, (p < 0.001 vs. controls). Levels of T and DHT in control liver tissue were < 0.2 pg/mg. CRPC in anorchid animals maintains tumoral androgen levels despite castration. 17β-estradiol significantly suppressed tumor T and DHT and inhibits growth of CRPC in an estrogen receptor independent manner. The ability to manipulate tumoral androgens will be critical in the development and testing of agents targeting CRPC through tissue steroidogenesis

Castration-Resistant Lgr5+ Cells Are Long-Lived Stem Cells Required for Prostatic Regeneration

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Bu-er Wang

2015-05-01

Full Text Available The adult prostate possesses a significant regenerative capacity that is of great interest for understanding adult stem cell biology. We demonstrate that leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5 is expressed in a rare population of prostate epithelial progenitor cells, and a castration-resistant Lgr5+ population exists in regressed prostate tissue. Genetic lineage tracing revealed that Lgr5+ cells and their progeny are primarily luminal. Lgr5+ castration-resistant cells are long lived and upon regeneration, both luminal Lgr5+ cells and basal Lgr5+ cells expand. Moreover, single Lgr5+ cells can generate multilineage prostatic structures in renal transplantation assays. Additionally, Lgr5+ cell depletion revealed that the regenerative potential of the castrated adult prostate depends on Lgr5+ cells. Together, these data reveal insights into the cellular hierarchy of castration-resistant Lgr5+ cells, indicate a requirement for Lgr5+ cells during prostatic regeneration, and identify an Lgr5+ adult stem cell population in the prostate.

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

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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.

AR copy number and AR signaling-directed therapies in castration-resistant prostate cancer.

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Salvi, Samanta; Conteduca, Vincenza; Lolli, Cristian; Testoni, Sara; Casadio, Valentina; Zaccheroni, Andrea; Rossi, Lorena; Burgio, Salvatore Luca; Menna, Cecilia; Schepisi, Giuseppe; De Giorgi, Ugo

2017-11-22

Adaptive upregulation of androgen receptor (AR) is the most common event involved in the progression from hormone sensitive to castration-resistant prostate cancer (CRPC). AR signaling remains the main target of new AR signalling-directed therapies such as abiraterone and enzalutamide in CRPC patients. In this review, we discuss general mechanisms of resistance to AR-targeted therapies, with a focus on the role of AR copy number (CN). We reported methods and clinical applications of AR CN evaluation in tissue and liquid biopsy, thus to have a complete information regarding its role as predictive and prognostic biomarker. Outcomes of CRPC patients are reported to be highly variable as consequence of tumor heterogeneity. AR CN could contribute to patient selection and tumor monitoring in CRPC treated with new anti-cancer treatment as abiraterone and enzalutamide. Further studies to investigate AR CN effect to these agents and its potential combination with other prognostic or predictive clinical factors are necessary in the context of harmonized clinical trial design. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Common structural and epigenetic changes in the genome of castration-resistant prostate cancer.

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Friedlander, Terence W; Roy, Ritu; Tomlins, Scott A; Ngo, Vy T; Kobayashi, Yasuko; Azameera, Aruna; Rubin, Mark A; Pienta, Kenneth J; Chinnaiyan, Arul; Ittmann, Michael M; Ryan, Charles J; Paris, Pamela L

2012-02-01

Progression of primary prostate cancer to castration-resistant prostate cancer (CRPC) is associated with numerous genetic and epigenetic alterations that are thought to promote survival at metastatic sites. In this study, we investigated gene copy number and CpG methylation status in CRPC to gain insight into specific pathophysiologic pathways that are active in this advanced form of prostate cancer. Our analysis defined and validated 495 genes exhibiting significant differences in CRPC in gene copy number, including gains in androgen receptor (AR) and losses of PTEN and retinoblastoma 1 (RB1). Significant copy number differences existed between tumors with or without AR gene amplification, including a common loss of AR repressors in AR-unamplified tumors. Simultaneous gene methylation and allelic deletion occurred frequently in RB1 and HSD17B2, the latter of which is involved in testosterone metabolism. Lastly, genomic DNA from most CRPC was hypermethylated compared with benign prostate tissue. Our findings establish a comprehensive methylation signature that couples epigenomic and structural analyses, thereby offering insights into the genomic alterations in CRPC that are associated with a circumvention of hormonal therapy. Genes identified in this integrated genomic study point to new drug targets in CRPC, an incurable disease state which remains the chief therapeutic challenge. ©2012 AACR.

Large Oncosomes: A Novel Liquid Biopsy for Genetic Profiling in Patients with Castration-Resistant Prostate Cancer

Science.gov (United States)

2017-09-01

Resistant Prostate Cancer PRINCIPAL INVESTIGATOR: Dolores Di Vizio, MD, PhD CONTRACTING ORGANIZATION: Cedars-Sinai Medical Center Los Angeles...Castration-Resistant Prostate Cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-16-1-0397 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Dolores Di...biopsy” changing the landscape of precision medicine. 15. SUBJECT TERMS Metastatic Castration Resistant Prostate Cancer , Extracellular Vesicles

Androgen-mediated development of irradiation-induced thyroid tumors in rats: dependence on animal age during interval of androgen replacement in castrated males

International Nuclear Information System (INIS)

Hofmann, C.; Oslapas, R.; Nayyar, R.; Paloyan, E.

1986-01-01

When male Long-Evans rats at age 8 weeks were radiation treated (40 microCi Na131I), thyroid follicular adenomas and carcinomas were observed at age 24 months with a high incidence of 94%. Castration of males prior to irradiation significantly reduced this tumor incidence to 60%. When testosterone (T) was replaced in castrated, irradiated male rats, differentially increased incidences of thyroid tumors occurred. Immediate (age 2-6 mo) or early (age 6-12 mo) T replacement at approximate physiologic levels led to thyroid follicular tumor incidences of 100 and 82%, respectively, whereas intermediate (12-18 mo) or late (18-24 mo) T treatment led to only 70 and 73% incidences, respectively. Continuous T replacement (2-24 mo) in castrated irradiated male rats raised thyroid tumor incidence to 100%. Since elevated thyroid-stimulating hormone (TSH) is a reported requisite for development of radiation-associated thyroid tumors, the effects of T on serum TSH levels were examined. Mean serum TSH values in all irradiated animal groups were significantly elevated above age-matched nonirradiated animals at 6, 12, 18, and 24 months. Serum TSH levels were higher in continuous T-replaced irradiated castrates than in intact, irradiated males, whereas such intact male TSH levels were greater than those for irradiated castrates without T treatment. Interval T replacement in castrated male rats was associated with increased serum TSH levels during the treatment interval and with lowered TSH levels after discontinuation of T treatment, particularly in irradiated rats. However, when irradiated, castrated males received late T replacement (age 18-24 mo), there was no elevation of TSH at the end of the treatment interval. An indirect effect of T via early stimulation of TSH may be partly responsible for the high incidence of irradiation-induced thyroid tumors in rats

A combination of sorafenib and nilotinib reduces the growth of castrate-resistant prostate cancer

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Archibald M

2016-01-01

Full Text Available Monica Archibald,1 Tara Pritchard,1 Hayley Nehoff,1 Rhonda J Rosengren,1 Khaled Greish,1,2 Sebastien Taurin1 1Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand; 2Aljawhara Centre for Molecular Medicine, Arabian Gulf University, Manama, Kingdom of Bahrain Abstract: Castrate-resistant prostate cancer (CRPC remains incurable due to the lack of effective therapies. Several tyrosine kinases have been implicated in the development and growth of CRPC, as such targeting these kinases may offer an alternative therapeutic strategy. We established the combination of two tyrosine kinase inhibitors (TKIs, sorafenib and nilotinib, as the most cytotoxic. In addtion, to improve their bioavailability and reduce their metabolism, we encapsulated sorafenib and nilotinib into styrene-co-maleic acid micelles. The micelles’ charge, size, and release rate were characterized. We assessed the effect of the combination on the cytotoxicity, cell cycle, apoptosis, protein expression, tumor spheroid integrity, migration, and invasion. The micelles exhibited a mean diameter of 100 nm, a neutral charge, and appeared highly stable. The micellar TKIs promoted greater cytotoxicity, decreased cell proliferation, and increased apoptosis relative to the free TKIs. In addition, the combination reduced the expression and activity of several tyrosine kinases and reduced tumor spheroid integrity and metastatic potential of CRPC cell lines more efficiently than the single treatments. The combination increased the therapeutic potential and demonstrated the relevance of a targeted combination therapy for the treatment of CRPC. In addition, the efficacy of the encapsulated drugs provides the basis for an in vivo preclinical testing. Keywords: sorafenib, nilotinib, castrate-resistant prostate cancer, tyrosine kinase inhibitors, nanomedicine

Free Testosterone During Androgen Deprivation Therapy Predicts Castration-Resistant Progression Better Than Total Testosterone.

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Regis, Lucas; Planas, Jacques; Carles, Joan; Maldonado, Xavier; Comas, Inma; Ferrer, Roser; Morote, Juan

2017-01-01

The optimal degree of testosterone suppression in patients with prostate cancer undergoing androgen deprivation therapy remains in question. Furthermore, serum free testosterone, which is the active form of testosterone, seems to correlate with intraprostatic testosterone. Here we compared free and total serum testosterone as predictors of survival free of castration resistance. Total testosterone (chemiluminescent assay, lower sensitivity 10 ng/dl) and free testosterone (analogue-ligand radioimmunoassay, lower sensitivity 0.05 pg/ml) were determined at 6 months of LHRH agonist treatment in a prospective cohort of 126 patients with prostate cancer. During a mean follow-up of 67 months (9-120), 75 (59.5%) events of castration-resistant progression were identified. Multivariate analysis and survival analysis according to total testosterone cutoffs of 50, 32, and 20 ng/dl, and free testosterone cutoffs of 1.7, 1.1, and 0.7 pg/ml were performed. Metastatic spread was the most powerful predictor of castration resistance, HR: 2.09 (95%CI: 1.18-3.72), P = 0.012. Gleason score, baseline PSA and PSA at 6 months were also independents predictors, but not free and total testosterone. Stratified analysis was conducted on the basis of the status of metastatic diseases and free testosterone was found to be an independent predictor of survival free of castration resistance in the subgroup of patients without metastasis, HR: 2.12 (95%CI: 1.16-3.85), P = 0.014. The lowest threshold of free testosterone which showed significant differences was 1.7 pg/ml, P = 0.003. Free testosterone at 6 months of LHRH agonist treatment seems to be a better surrogate than total testosterone to predict castration resistance in no metastatic prostate cancer patients. Prostate 77:114-120, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Phenotypic and genetic heterogeneity of tumor tissue and circulating tumor cells in patients with metastatic castration-resistant prostate cancer: A report from the PETRUS prospective study.

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Massard, Christophe; Oulhen, Marianne; Le Moulec, Sylvestre; Auger, Nathalie; Foulon, Stéphanie; Abou-Lovergne, Aurélie; Billiot, Fanny; Valent, Alexander; Marty, Virginie; Loriot, Yohann; Fizazi, Karim; Vielh, Philippe; Farace, Francoise

2016-08-23

Molecular characterization of cancer samples is hampered by tumor tissue availability in metastatic castration-resistant prostate cancer (mCRPC) patients. We reported the results of prospective PETRUS study of biomarker assessment in paired primary prostatic tumors, metastatic biopsies and circulating tumor cells (CTCs). Among 54 mCRPC patients enrolled, 38 (70%) had biopsies containing more than 50% tumour cells. 28 (52%) patients were analyzed for both tissue samples and CTCs. FISH for AR-amplification and TMPRSS2-ERG translocation were successful in 54% and 32% in metastatic biopsies and primary tumors, respectively. By comparing CellSearch and filtration (ISET)-enrichment combined to four color immunofluorescent staining, we showed that CellSearch and ISET isolated distinct subpopulations of CTCs: CTCs undergoing epithelial-to-mesenchymal transition, CTC clusters and large CTCs with cytomorphological characteristics but no detectable markers were isolated using ISET. Epithelial CTCs detected by the CellSearch were mostly lost during the ISET-filtration. AR-amplification was detected in CellSearch-captured CTCs, but not in ISET-enriched CTCs which harbor exclusively AR gain of copies. Eighty-eight percent concordance for ERG-rearrangement was observed between metastatic biopsies and CTCs even if additional ERG-alteration patterns were detected in ISET-enriched CTCs indicating a higher heterogeneity in CTCs.Molecular screening of metastatic biopsies is achievable in a multicenter context. Our data indicate that CTCs detected by the CellSearch and the ISET-filtration systems are not only phenotypically but also genetically different. Close attention must be paid to CTC characterization since neither approach tested here fully reflects the tremendous phenotypic and genetic heterogeneity present in CTCs from mCRPC patients.

Weekly ascorbic acid infusion in castration-resistant prostate cancer patients

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Nielsen, Torben K.; Højgaard, Martin; Andersen, Jon T.

2017-01-01

of this treatment.  Methods: This non-comparative, single-center, phase II trial included patients with chemotherapy-naïve, metastatic castration-resistant prostate cancer (mCRPC) from an outpatient clinic to evaluate the efficacy and safety of IV AA therapy. Patients received weekly infusions of AA (week 1, 5 g...... μg/L was recorded at week 12. Among the secondary endpoints, no signs of disease remission were observed. In total, 53 adverse events (AEs) were recorded. Eleven were graded as "serious". Three AEs were directly related to AA, and all of which were related to fluid load.  Conclusions: Infusion...

Castration-resistant prostate cancer: AUA Guideline.

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Cookson, Michael S; Roth, Bruce J; Dahm, Philipp; Engstrom, Christine; Freedland, Stephen J; Hussain, Maha; Lin, Daniel W; Lowrance, William T; Murad, Mohammad Hassan; Oh, William K; Penson, David F; Kibel, Adam S

2013-08-01

This Guideline is intended to provide a rational basis for the management of patients with castration-resistant prostate cancer based on currently available published data. A systematic review and meta-analysis of the published literature was conducted using controlled vocabulary supplemented with keywords relating to the relevant concepts of prostate cancer and castration resistance. The search strategy was developed and executed by reference librarians and methodologists to create an evidence report limited to English-language, published peer-reviewed literature. This review yielded 303 articles published from 1996 through 2013 that were used to form a majority of the guideline statements. Clinical Principles and Expert Opinions were used for guideline statements lacking sufficient evidence-based data. Guideline statements were created to inform clinicians on the appropriate use of observation, androgen-deprivation and antiandrogen therapy, androgen synthesis inhibitors, immunotherapy, radionuclide therapy, systemic chemotherapy, palliative care and bone health. These were based on six index patients developed to represent the most common scenarios encountered in clinical practice. As a direct result of the significant increase in FDA-approved therapeutic agents for use in patients with metastatic CRPC, clinicians are challenged with a multitude of treatment options and potential sequencing of these agents that, consequently, make clinical decision-making more complex. Given the rapidly evolving nature of this field, this guideline should be used in conjunction with recent systematic literature reviews and an understanding of the individual patient's treatment goals. In all cases, patients' preferences and personal goals should be considered when choosing management strategies. Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

A Pharmacokinetic/Pharmacodynamic Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined with Enzalutamide in Castrate-Resistant Prostate Cancer

Science.gov (United States)

2017-12-01

Receptor Antagonist Mifepristone Combined with Enzalutamide in Castrate-Resistant Prostate Cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER... receptor (AR) targeted therapies, prostate cancer adapts. One way it adapts is by upregulating another hormone receptor , the glucocorticoid receptor (GR...trial. 15. SUBJECT TERMS Castration resistant prostate cancer (CRPC); Androgen Receptor (AR); Glucocorticoid receptor (GR); Enzalutamide;

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

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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.

Weekly ascorbic acid infusion in castration-resistant prostate cancer patients

DEFF Research Database (Denmark)

Nielsen, Torben K.; Højgaard, Martin; Andersen, Jon T.

2017-01-01

of this treatment. Methods: This non-comparative, single-center, phase II trial included patients with chemotherapy-naïve, metastatic castration-resistant prostate cancer (mCRPC) from an outpatient clinic to evaluate the efficacy and safety of IV AA therapy. Patients received weekly infusions of AA (week 1, 5 g....../L was recorded at week 12. Among the secondary endpoints, no signs of disease remission were observed. In total, 53 adverse events (AEs) were recorded. Eleven were graded as "serious". Three AEs were directly related to AA, and all of which were related to fluid load. Conclusions: Infusion with 60 g of AA did...

Restoration of the cellular secretory milieu overrides androgen dependence of in vivo generated castration resistant prostate cancer cells overexpressing the androgen receptor.

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Patki, Mugdha; Huang, Yanfang; Ratnam, Manohar

2016-07-22

It is believed that growth of castration resistant prostate cancer (CRPC) cells is enabled by sensitization to minimal residual post-castrate androgen due to overexpression of the androgen receptor (AR). Evidence is derived from androgen-induced colony formation in the absence of cell-secreted factors or from studies involving forced AR overexpression in hormone-dependent cells. On the other hand, standard cell line models established from CRPC patient tumors (e.g., LNCaP and VCaP) are hormone-dependent and require selection pressure in castrated mice to re-emerge as CRPC cells and the resulting tumors then tend to be insensitive to the androgen antagonist enzalutamide. Therefore, we examined established CRPC model cells produced by castration of mice bearing hormone-dependent cell line xenografts including CRPC cells overexpressing full-length AR (C4-2) or co-expressing wtAR and splice-variant AR-V7 that is incapable of ligand binding (22Rv1). In standard colony formation assays, C4-2 cells were shown to be androgen-dependent and sensitive to enzalutamide whereas 22Rv1 cells were incapable of colony formation under identical conditions. However, both C4-2 and 22Rv1 cells formed colonies in conditioned media derived from the same cells or from HEK293 fibroblasts that were proven to lack androgenic activity. This effect was (i) not enhanced by androgen, (ii) insensitive to enzalutamide, (iii) dependent on AR (in C4-2) and on AR-V7 and wtAR (in 22Rv1) and (iv) sensitive to inhibitors of several signaling pathways, similar to androgen-stimulation. Therefore, during progression to CRPC in vivo, coordinate cellular changes accompanying overexpression of AR may enable cooperation between hormone-independent activity of AR and actions of cellular secretory factors to completely override androgen-dependence and sensitivity to drugs targeting hormonal factors. Copyright © 2016 Elsevier Inc. All rights reserved.

Abiraterone acetate for patients with metastatic castration-resistant prostate cancer progressing after chemotherapy

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Sternberg, Cora N; Castellano, Daniel; Daugaard, Gedske

2014-01-01

, development of sustained side-effects, or abiraterone acetate becoming available in the respective country. The primary outcome was the number of adverse events arising during study treatment and within 30 days of discontinuation. Efficacy measures (time to prostate-specific antigen [PSA] progression and time......BACKGROUND: In the final analysis of the phase 3 COU-AA-301 study, abiraterone acetate plus prednisone significantly prolonged overall survival compared with prednisone alone in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy. Here, we present the final...... analysis of an early-access protocol trial that was initiated after completion of COU-AA-301 to enable worldwide preapproval access to abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy. METHODS: We did a multicentre, open-label, early...

Enzalutamide in Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer

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Beer, Tomasz M; Armstrong, Andrew J; Rathkopf, Dana

2017-01-01

Enzalutamide significantly improved radiographic progression-free survival (rPFS) and overall survival (OS) among men with chemotherapy-naïve metastatic castration-resistant prostate cancer at the prespecified interim analysis of PREVAIL, a phase 3, double-blind, randomized study. We evaluated...

Molecular biology of castration-resistant prostate cancer: basis for the novel therapeutic targets.

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Mellado, Begoña; Marin Aguilera, Mercedes; Pereira, Maria Veronica

2013-06-01

Prostate cancer cells express the androgen receptor (AR) and need the presence of androgens to survive. Androgen suppression is the gold standard first-line therapy for metastatic disease. Almost all prostate cancer patients initially respond to hormonal therapy, but most of them gradually develop castration-resistant progression. Recent evidence has shown that progression at the castration resistant prostate cancer (CRPC) stage is often mediated by AR signalling. Importantly, subsequent AR androgen inhibition, by abiraterone acetate or enzalutamide, has shown to improve patients' survival. Several mechanisms that enhance AR signalling in an androgen-depleted environment have been elucidated:(1) AR mutations that allow activation by low androgen levels or by other endogenous steroids, (2) AR amplification and/or overexpression,(3)increased local intracrine synthesis of androgens, (4) changes in AR cofactors and (5) cross-talk with cytokines and growth factors. Today, there are under development a number of novel agents targeting the AR signaling pathway. This article reviews the postulated mechanisms of AR-driven resistance to androgen suppression that have contributed to the development of new hormonal therapeutic strategies in prostate cancer.

Overview of treatment of castration-resistant prostate cancer

International Nuclear Information System (INIS)

Obertova, J.

2012-01-01

Prostatic cancer is a very heterogenic disease. Initial treatment of metastatic disease is androgen deprivation therapy, however upon the time eventually all cases develop castrate resistant disease (CRCP). In CRPC the combination of docetaxel with prednisone is considered to be the gold standard first line therapy with prolongation of overall survival. Until recently there was not standardly defined second line treatment. According to the international guidelines of today cabazitaxel and abirateron is recommended as second line therapy. The objective of this article is to present a review of the therapy of CRPC upon results from randomised phase III clinical trials. (author)

Abiraterone acetate: oral androgen biosynthesis inhibitor for treatment of castration-resistant prostate cancer

Directory of Open Access Journals (Sweden)

Rosenberg JE

2012-01-01

Full Text Available Yasser Rehman1, Jonathan E Rosenberg21Division of Hospital Medicine, UMass Memorial Healthcare, Worcester, MA, USA; 2Lank Center for Genitourinary Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USAAbstract: Prostate cancer is the second leading cause of cancer death in men in the US and Europe. The treatment of advanced-stage prostate cancer has been androgen deprivation. Medical castration leads to decreased production of testosterone and dihydrotestosterone by the testes, but adrenal glands and even prostate cancer tissue continue to produce androgens, which eventually leads to continued prostate cancer growth despite castrate level of androgens. This stage is known as castrate-resistant prostate cancer (CRPC, which continues to be a challenge to treat. Addition of androgen antagonists to hormonal deprivation has been successful in lowering the prostate-specific antigen levels further, but has not actually translated into life-prolonging options. The results of several contemporary studies have continued to demonstrate activation of the androgen receptor as being the key factor in the continued growth of prostate cancer. Blockade of androgen production by nongonadal sources has led to clinical benefit in this setting. One such agent is abiraterone acetate, which significantly reduces androgen production by blocking the enzyme, cytochrome P450 17 alpha-hydroxylase (CYP17. This has provided physicians with another treatment option for patients with CRPC. The landscape for prostate cancer treatment has changed with the approval of cabazitaxel, sipuleucel-T and abiraterone. Here we provide an overview of abiraterone acetate, its mechanism of action, and its potential place for therapy in CRPC.Keywords: CRPC, abiraterone, CYP17, inhibitors, androgens, castration resistant prostate cancer

Docetaxel, Carboplatin, and Rucaparib Camsylate in Treating Patients With Metastatic Castration Resistant Prostate Cancer With Homologous Recombination DNA Repair Deficiency

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2018-02-20

ATM Gene Mutation; BRCA1 Gene Mutation; BRCA2 Gene Mutation; Castration Levels of Testosterone; Castration-Resistant Prostate Carcinoma; Homologous Recombination Deficiency; Prostate Carcinoma Metastatic in the Bone; PSA Level Greater Than or Equal to Two; PSA Progression; Stage IV Prostate Adenocarcinoma AJCC v7

Prostate Cancer Stem-like Cells Contribute to the Development of Castration-Resistant Prostate Cancer

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Diane Ojo

2015-11-01

Full Text Available Androgen deprivation therapy (ADT has been the standard care for patients with advanced prostate cancer (PC since the 1940s. Although ADT shows clear benefits for many patients, castration-resistant prostate cancer (CRPC inevitably occurs. In fact, with the two recent FDA-approved second-generation anti-androgens abiraterone and enzalutamide, resistance develops rapidly in patients with CRPC, despite their initial effectiveness. The lack of effective therapeutic solutions towards CRPC largely reflects our limited understanding of the underlying mechanisms responsible for CRPC development. While persistent androgen receptor (AR signaling under castration levels of serum testosterone (<50 ng/mL contributes to resistance to ADT, it is also clear that CRPC evolves via complex mechanisms. Nevertheless, the physiological impact of individual mechanisms and whether these mechanisms function in a cohesive manner in promoting CRPC are elusive. In spite of these uncertainties, emerging evidence supports a critical role of prostate cancer stem-like cells (PCSLCs in stimulating CRPC evolution and resistance to abiraterone and enzalutamide. In this review, we will discuss the recent evidence supporting the involvement of PCSLC in CRPC acquisition as well as the pathways and factors contributing to PCSLC expansion in response to ADT.

Targeted α-Therapy of Metastatic Castration-Resistant Prostate Cancer with 225Ac-PSMA-617: Swimmer-Plot Analysis Suggests Efficacy Regarding Duration of Tumor Control.

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Kratochwil, Clemens; Bruchertseifer, Frank; Rathke, Hendrik; Hohenfellner, Markus; Giesel, Frederik L; Haberkorn, Uwe; Morgenstern, Alfred

2018-05-01

The aim of this evaluation was to identify the first indicators of efficacy for 225 Ac-labeled prostate-specific membrane antigen (PSMA)-617 therapy in a retrospectively analyzed group of patients. Methods: Forty patients with metastatic castration-resistant prostate cancer were selected for treatment with three 100 kBq/kg cycles of 225 Ac-PSMA-617 at 2-mo intervals. Prostate-specific antigen (PSA) and blood cell count were measured every 4 wk. PSMA PET/CT or PSMA SPECT/CT were used for baseline staging and imaging follow-up at month 6. Follow-up included the duration of PSA response and radiologic progression-free survival at month 6. Patient histories were reviewed for the duration of previous treatment lines, and a swimmer plot was used to intraindividually compare the duration of tumor control by PSMA therapy versus prior treatment modalities. Results: Thirty-one of 40 patients were treated per protocol. Five patients discontinued treatment because of nonresponse, and 4 because of xerostomia. Of the 38 patients surviving at least 8 wk, 24 (63%) had a PSA decline of more than 50%, and 33 (87%) had a PSA response of any degree. The median duration of tumor control under 225 Ac-PSMA-617 last-line therapy was 9.0 mo; 5 patients had an enduring response of more than 2 y. Because all patients had advanced disease, this result compares favorably with the tumor control rates associated with earlier-phase disease; the most common preceding first-, second-, third-, and fourth-line therapies were abiraterone (median duration 10.0 mo), docetaxel (6.5 mo), enzalutamide (6.5 mo), and cabazitaxel (6.0 mo), respectively. Conclusion: A positive response for surrogate parameters demonstrates remarkable antitumor activity for 225 Ac-PSMA-617. Swimmer-plot analysis indicates a promising duration of tumor control, especially considering the unfavorable prognostic profile of the selected advanced-stage patients. Xerostomia was the main reason patients discontinued therapy or refused

A single-center experience with abiraterone as treatment for metastatic castration-resistant prostate cancer

DEFF Research Database (Denmark)

Thortzen, Anita; Thim, Stine; Røder, Martin Andreas

2016-01-01

BACKGROUND: Continuous stimulation of the androgen receptor (AR) axis is a prerequisite for growth in castration-resistant prostate cancer (CRPC). Abiraterone acetate (AA) is a potent inhibitor of extracellular and intracellular androgen synthesis by inhibition of the CYP-17 enzyme system, which...... at Rigshospitalet, Denmark, and compare the results with phase III trial outcomes. MATERIAL AND METHODS: Single-centre, retrospective study including consecutive patients managed on AA for more than 2-year period. Treatment consisted of 1,000mg AA and 5mg prednisone twice daily. Outcomes of interest were prostate...

The PREVAIL Study: Primary Outcomes by Site and Extent of Baseline Disease for Enzalutamide-treated Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer.

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Evans, Christopher P; Higano, Celestia S; Keane, Thomas; Andriole, Gerald; Saad, Fred; Iversen, Peter; Miller, Kurt; Kim, Choung-Soo; Kimura, Go; Armstrong, Andrew J; Sternberg, Cora N; Loriot, Yohann; de Bono, Johann; Noonberg, Sarah B; Mansbach, Hank; Bhattacharya, Suman; Perabo, Frank; Beer, Tomasz M; Tombal, Bertrand

2016-10-01

Enzalutamide, an oral androgen receptor inhibitor, significantly improved overall survival (OS) and radiographic progression-free survival (rPFS) versus placebo in the PREVAIL trial of men with chemotherapy-naïve metastatic castration-resistant prostate cancer. To assess the effects of enzalutamide versus placebo in patients from PREVAIL based on site and extent of baseline disease. One thousand seven hundred and seventeen asymptomatic or minimally symptomatic patients were randomized to enzalutamide (n=872) or placebo (n=845). Subgroup analyses included nonvisceral (only bone and/or nodal; n=1513), visceral (lung and/or liver; n=204), low-volume bone disease (1 in patients with visceral disease (HR, 0.82; 95% CI, 0.55-1.23). Enzalutamide was well tolerated in patients with or without visceral disease. Enzalutamide provided clinically significant benefits in men with chemotherapy-naïve metastatic castration-resistant prostate cancer, with or without visceral disease, low- or high-volume bone disease, or lymph node only disease. Patients with metastatic castration-resistant prostate cancer-including those with or without visceral disease or widespread bone disease-benefitted from enzalutamide, an active well-tolerated therapy. Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Safety of cabazitaxel in senior adults with metastatic castration-resistant prostate cancer

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Heidenreich, Axel; Bracarda, Sergio; Mason, Malcolm

2014-01-01

BACKGROUND: Cabazitaxel/prednisone has been shown to prolong survival versus mitoxantrone/prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) that has progressed during or after docetaxel. Subsequently, compassionate-use programmes (CUPs) and expanded-access progra......-CSF, especially at cycle 1 and in men aged > or =75 years, is important and improves tolerability in senior adults treated with cabazitaxel....

Lycopene Enhances Docetaxel's Effect in Castration-Resistant Prostate Cancer Associated with Insulin-like Growth Factor I Receptor Levels1

Science.gov (United States)

Tang, Yaxiong; Parmakhtiar, Basmina; Simoneau, Anne R; Xie, Jun; Fruehauf, John; Lilly, Michael; Zi, Xiaolin

2011-01-01

Docetaxel is currently the most effective drug for the treatment of castration-resistant prostate cancer (CRPC), but it only extends life by an average of 2 months. Lycopene, an antioxidant phytochemical, has antitumor activity against prostate cancer (PCa) in several models and is generally safe. We present data on the interaction between docetaxel and lycopene in CRPC models. The growth-inhibitory effect of lycopene on PCa cell lines was positively associated with insulin-like growth factor I receptor (IGF-IR) levels. In addition, lycopene treatment enhanced the growth-inhibitory effect of docetaxel more effectively on DU145 cells with IGF-IR high expression than on those PCa cell lines with IGF-IR low expression. In a DU145 xenograft tumor model, docetaxel plus lycopene caused tumor regression, with a 38% increase in antitumor efficacy (P = .047) when compared with docetaxel alone. Lycopene inhibited IGF-IR activation through inhibiting IGF-I stimulation and by increasing the expression and secretion of IGF-BP3. Downstream effects include inhibition of AKT kinase activity and survivin expression, followed by apoptosis. Together, the enhancement of docetaxel's antitumor efficacy by lycopene supplementation justifies further clinical investigation of lycopene and docetaxel combination for CRPC patients. CRPC patients with IGF-IR-overexpressing tumors may be most likely to benefit from this combination. PMID:21403837

Disease Progression/Clinical Outcome Model for Castration-Resistant Prostate Cancer in Patients Treated with Eribulin

NARCIS (Netherlands)

Van Hasselt, J. G C; Gupta, A.; Hussein, Z.; Beijnen, J. H.; Schellens, J. H M; Huitema, A. D R

2015-01-01

Frameworks that associate cancer dynamic disease progression models with parametric survival models for clinical outcome have recently been proposed to support decision making in early clinical development. Here we developed such a disease progression clinical outcome model for castration-resistant

Cabazitaxel as second-line or third-line therapy in patients with metastatic castration-resistant prostate cancer

DEFF Research Database (Denmark)

Kongsted, Per; Svane, Inge M; Lindberg, Henriette

2016-01-01

To compare treatment outcomes in patients with metastatic castration-resistant prostate cancer treated with cabazitaxel (CA) as second-line or third-line therapy in the everyday clinical setting. Charts from 94 patients treated with CA as second-line (n=28) or third-line therapy (n=66) were...... evaluated. Common Terminology Criteria for Adverse Events were used to register grade 3-4 nonhematological toxicity during treatment with CA. Baseline metastatic castration-resistant prostate cancer-related prognostic factors, duration of therapy, and maximum prostate-specific antigen (PSA) percentage...... change were registered during treatment with CA and previous/subsequent novel androgen receptor targeting therapies. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. A median of 6 versus 5 treatment cycles was administered in patients treated...

Resistance to BET Inhibitor Leads to Alternative Therapeutic Vulnerabilities in Castration-Resistant Prostate Cancer.

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Pawar, Aishwarya; Gollavilli, Paradesi Naidu; Wang, Shaomeng; Asangani, Irfan A

2018-02-27

BRD4 plays a major role in the transcription networks orchestrated by androgen receptor (AR) in castration-resistant prostate cancer (CRPC). Several BET inhibitors (BETi) that displace BRD4 from chromatin are being evaluated in clinical trials for CRPC. Here, we describe mechanisms of acquired resistance to BETi that are amenable to targeted therapies in CRPC. BETi-resistant CRPC cells displayed cross-resistance to a variety of BETi in the absence of gatekeeper mutations, exhibited reduced chromatin-bound BRD4, and were less sensitive to BRD4 degraders/knockdown, suggesting a BRD4-independent transcription program. Transcriptomic analysis revealed reactivation of AR signaling due to CDK9-mediated phosphorylation of AR, resulting in sensitivity to CDK9 inhibitors and enzalutamide. Additionally, increased DNA damage associated with PRC2-mediated transcriptional silencing of DDR genes was observed, leading to PARP inhibitor sensitivity. Collectively, our results identify the therapeutic limitation of BETi as a monotherapy; however, our BETi resistance data suggest unique opportunities for combination therapies in treating CRPC. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Radiographic progression with nonrising PSA in metastatic castration-resistant prostate cancer

DEFF Research Database (Denmark)

Bryce, A H; Alumkal, J J; Armstrong, A

2017-01-01

monitoring alone to determine disease status on therapy. This approach has not been adequately tested. METHODS: Chemotherapy-naive asymptomatic or mildly symptomatic men (n=872) with metastatic castration-resistant prostate cancer (mCRPC) who were treated with the androgen receptor inhibitor enzalutamide......BACKGROUND: Advanced prostate cancer is a phenotypically diverse disease that evolves through multiple clinical courses. PSA level is the most widely used parameter for disease monitoring, but it has well-recognized limitations. Unlike in clinical trials, in practice, clinicians may rely on PSA...... treated with enzalutamide. As restaging in advanced prostate cancer patients is often guided by increases in PSA levels, our results demonstrate that disease progression on enzalutamide can occur without rising PSA levels. Therefore, a disease monitoring strategy that includes imaging not entirely reliant...

Epigenetic Machinery Regulates Alternative Splicing of Androgen Receptor (AR) Gene in Castration Resistant Prostate Cancer

Science.gov (United States)

2017-09-01

resistant prostate cancer PRINCIPAL INVESTIGATOR: Zhi-Ping Liu CONTRACTING ORGANIZATION: UT Southwestern Medical Center Dallas, TX 75390 REPORT DATE...NUMBER gene in castration-resistant prostate cancer 5b. GRANT NUMBER W81XWH-16-1-0531 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Zhi-Ping Liu 5d...NOTES 14. ABSTRACT Androgen deprivation therapy (ADT) is the primary treatment for metastatic prostate cancer (PCa) since PCa depends on androgen for

Androgen Receptor Antagonism By Divalent Ethisterone Conjugates In Castrate-Resistant Prostate Cancer Cells

Science.gov (United States)

Levine, Paul M.; Lee, Eugine; Greenfield, Alex; Bonneau, Richard; Logan, Susan K.; Garabedian, Michael J.; Kirshenbaum, Kent

2013-01-01

Sustained treatment of prostate cancer with Androgen Receptor (AR) antagonists can evoke drug resistance, leading to castrate-resistant disease. Elevated activity of the AR is often associated with this highly aggressive disease state. Therefore, new therapeutic regimens that target and modulate AR activity could prove beneficial. We previously introduced a versatile chemical platform to generate competitive and non-competitive multivalent peptoid oligomer conjugates that modulate AR activity. In particular, we identified a linear and a cyclic divalent ethisterone conjugate that exhibit potent anti-proliferative properties in LNCaP-abl cells, a model of castrate-resistant prostate cancer. Here, we characterize the mechanism of action of these compounds utilizing confocal microscopy, time-resolved fluorescence resonance energy transfer, chromatin immunoprecipitation, flow cytometry, and microarray analysis. The linear conjugate competitively blocks AR action by inhibiting DNA binding. In addition, the linear conjugate does not promote AR nuclear localization or co-activator binding. In contrast, the cyclic conjugate promotes AR nuclear localization and induces cell-cycle arrest, despite its inability to compete against endogenous ligand for binding to AR in vitro. Genome-wide expression analysis reveals that gene transcripts are differentially affected by treatment with the linear or cyclic conjugate. Although the divalent ethisterone conjugates share extensive chemical similarities, we illustrate that they can antagonize the AR via distinct mechanisms of action, establishing new therapeutic strategies for potential applications in AR pharmacology. PMID:22871957

Understanding the Role of MDSCs in Castration-Resistant Prostate Cancer and Metastasis

Science.gov (United States)

2016-12-01

MRI  analysis   (data  not   shown).  There   is  no  noticeable   normal   epithelium   in   the   castrated   Ptenpc...recruitment  of  MDSCs  to  the  TME  of   Ptenpc-­‐/-­‐Smad4pc-­‐/-­‐  tumors,  we  assessed  the  impact  of   pharmacologic ...B 9 Methodology:   We   used   pharmacological   approach   to   inhibit   CXCL5   and

Noninvasive Detection of AR-FL/AR-V7 as a Predictive Biomarker for Therapeutic Resistance in Men with Metastatic Castration-Resistant Prostate Cancer

Science.gov (United States)

2017-10-01

acknowledged federal support) 5. Antonarakis ES, Armstrong AJ, Dehm SM, Luo J. Androgen receptor variant-driven prostate cancer : clinical implications...Resistant Prostate Cancer abstract Purpose A splice variant of the androgen receptor , AR-V7, confers resistance to AR-targeted therapies (ATTs) but not...androgen receptor ; AR-V7, androgen receptor splice variant 7; mCRPC, metastatic castration-resistant prostate cancer ; n/N, number of patients in that

The Stromal Contribution to the Development of Resistance to New-Generation Drugs by Castration-Resistant Prostate Cancer

Science.gov (United States)

2015-10-01

abiraterone treatment by further increasing their expressions of steroidogenic genes and by further increasing their outputs of T and DHT . Finally, we...support (stromal) cells within a bone metastasis have a supportive role in the development of CRPC through their ability to synthesize T and DHT upon Hh...dihydrotestosterone ( DHT ) (3, 9-11). 4 After ADT, recurrence as castration-resistant disease is common (8). For PCa, the most common site for metastasis is bone

Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial

DEFF Research Database (Denmark)

de Bono, Johann Sebastian; Oudard, Stephane; Ozguroglu, Mustafa

2010-01-01

Cabazitaxel is a novel tubulin-binding taxane drug with antitumour activity in docetaxel-resistant cancers. We aimed to compare the efficacy and safety of cabazitaxel plus prednisone with those of mitoxantrone plus prednisone in men with metastatic castration-resistant prostate cancer with progre...

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.

The Role of PCA 3 as a Prognostic Factor in Patients with Castration-resistant Prostate Cancer (CRPC) Treated with Docetaxel.

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Bourdoumis, Andreas; Chrisofos, Michael; Stasinou, Theodora; Christopoulos, Panagiotis; Mourmouris, Panagiotis; Kostakopoulos, Athanasios; Deliveliotis, Charalambos

2015-05-01

To investigate potential fluctuations in prostate cancer antigen 3 (PCA 3) scores in castration-resistant prostate cancer (CRPC) patients treated with docetaxel and investigate the assay as a potential prognostic factor. This was a prospective observational cohort study. Inclusion criteria included patients on hormonal treatment who were recently diagnosed with CRPC. Exclusion criteria included patients previously having radical treatment (surgery or radiotherapy) and patients who have completed the first cycle of chemotherapy. All urine samples were collected and analyzed using the Progensa® assay. Samples were collected before starting chemotherapy and at 12 months. A prospective database was created including routine blood tests, prostate staging and prostate-specific antigen (PSA) levels throughout the study period. The effects of chemotherapy were also recorded. Between January 2010 and February 2013, 12 patients were included in the study out of an initial cohort of 23 patients with CRPC. Mean follow-up was 14.8 months. Mean age at CRPC diagnosis was 73.8 years (±3.6 SD). Mean Gleason score was 8, with PSA 84.23 ng/ml (±158 SD). Mean duration of androgen deprivation treatment (ADT) was 45.16 months (±34.9 SD). Mean time to castrate-resistant state was 46.58 months (±35.3 SD). All twelve (n=12, 100%) patients had non-assessable PCA 3 scores at baseline and at 12 months follow-up. As a direct consequence, statistical analysis was not performed as the anticipated change in PCA 3 scores was not identified and correlation between measurable differences was not possible. All patients tolerated chemotherapy and completed the scheduled cycles with no serious adverse effects. To our knowledge, this is the first prospective study to demonstrate lack of expression of PCA3 in CRPC, with the result apparently not influenced by chemotherapy. There appears to be a strong association between hormonal treatment and lack of PCA 3 expression. It is still unknown whether

Enzalutamide in Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer: Extended Analysis of the Phase 3 PREVAIL Study.

Science.gov (United States)

Beer, Tomasz M; Armstrong, Andrew J; Rathkopf, Dana; Loriot, Yohann; Sternberg, Cora N; Higano, Celestia S; Iversen, Peter; Evans, Christopher P; Kim, Choung-Soo; Kimura, Go; Miller, Kurt; Saad, Fred; Bjartell, Anders S; Borre, Michael; Mulders, Peter; Tammela, Teuvo L; Parli, Teresa; Sari, Suha; van Os, Steve; Theeuwes, Ad; Tombal, Bertrand

2017-02-01

Enzalutamide significantly improved radiographic progression-free survival (rPFS) and overall survival (OS) among men with chemotherapy-naïve metastatic castration-resistant prostate cancer at the prespecified interim analysis of PREVAIL, a phase 3, double-blind, randomized study. We evaluated the longer-term efficacy and safety of enzalutamide up to the prespecified number of deaths in the final analysis, which included an additional 20 mo of follow-up for investigator-assessed rPFS, 9 mo of follow-up for OS, and 4 mo of follow-up for safety. Enzalutamide reduced the risk of radiographic progression or death by 68% (hazard ratio [HR] 0.32, 95% confidence interval [CI] 0.28-0.37; pPREVAIL provides more complete assessment of the clinical benefit of enzalutamide. PREVAIL is registered on ClinicalTrials.gov as NCT01212991. According to data from longer follow-up, enzalutamide continued to provide benefit over placebo in patients with metastatic castration-resistant prostate cancer. Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Targeting Alternative Sites on the Androgen Receptor to Treat Castration-Resistant Prostate Cancer

Directory of Open Access Journals (Sweden)

Paul S. Rennie

2013-06-01

Full Text Available Recurrent, metastatic prostate cancer continues to be a leading cause of cancer-death in men. The androgen receptor (AR is a modular, ligand-inducible transcription factor that regulates the expression of genes that can drive the progression of this disease, and as a consequence, this receptor is a key therapeutic target for controlling prostate cancer. The current drugs designed to directly inhibit the AR are called anti-androgens, and all act by competing with androgens for binding to the androgen/ligand binding site. Unfortunately, with the inevitable progression of the cancer to castration resistance, many of these drugs become ineffective. However, there are numerous other regulatory sites on this protein that have not been exploited therapeutically. The regulation of AR activity involves a cascade of complex interactions with numerous chaperones, co-factors and co-regulatory proteins, leading ultimately to direct binding of AR dimers to specific DNA androgen response elements within the promoter and enhancers of androgen-regulated genes. As part of the family of nuclear receptors, the AR is organized into modular structural and functional domains with specialized roles in facilitating their inter-molecular interactions. These regions of the AR present attractive, yet largely unexploited, drug target sites for reducing or eliminating androgen signaling in prostate cancers. The design of small molecule inhibitors targeting these specific AR domains is only now being realized and is the culmination of decades of work, including crystallographic and biochemistry approaches to map the shape and accessibility of the AR surfaces and cavities. Here, we review the structure of the AR protein and describe recent advancements in inhibiting its activity with small molecules specifically designed to target areas distinct from the receptor’s androgen binding site. It is anticipated that these new classes of anti-AR drugs will provide an additional

Sipuleucel-T: Autologous Cellular Immunotherapy for Men with Asymptomatic or Minimally Symptomatic Metastatic Castrate Resistant Prostate Cancer

Directory of Open Access Journals (Sweden)

Robert B. Sims

2011-01-01

Full Text Available Sipuleucel T is an autologous cellular immunotherapy designed to stimulate an immune response in men diagnosed with asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory prostate cancer. Sipuleucel T improves overall survival and provides an additional treatment option for this patient population.

Open standing castration in Thoroughbred racehorses in Hong Kong: Prevalence and severity of complications 30 days post-castration.

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Rosanowski, S M; MacEoin, F; Graham, R J T Y; Riggs, C M

2018-05-01

Complications following open standing castration (OSC) in Thoroughbred racehorses are well recognised but variation in their prevalence and severity between populations is not well documented. To describe the prevalence and severity of complications in the 30 days following OSC. A retrospective cohort study of veterinary clinical records relating to horses that underwent OSC between July 2007 and July 2012. Complications were graded on a severity score from N, no complications, to C3, severe complications. Additional data were accessed for each horse including age, import date, racing history, trainer and veterinarian performing the castration. Bacterial culture and antimicrobial sensitivities were performed on a limited number of castration wounds that became infected. In total, 250 horses were castrated in Hong Kong using the OSC technique over the period of the study. Sixty percent (150/250) of horses experienced some type of post-castration complication, with eight horses experiencing a severe (C3) complication requiring intensive veterinary treatment. Scrotal swelling, funiculitis and seroma formation were present in 70.0%, 36.7% and 24.7% of cases respectively. Most horses experiencing complications required wound reopening (87.3%; 131/150), and/or an extended course of first-line antimicrobials and/or nonsteroidal anti-inflammatory drugs (75/150; 50.0%). Eight horses had cultures submitted for bacterial sensitivity, with 17 bacterial isolates grown. In vitro, the bacteria cultured were sensitive to enrofloxacin (76%; 13/17) and ceftiofur (100%; 17/17). Resistance was detected to penicillin, gentamicin, oxytetracycline, metronidazole and trimethoprim-sulfadiazine. Differences in post-castration management cannot be accounted for in this study. Complications following OSC in horses in Hong Kong were common. The majority were mild and were successfully treated using antimicrobials and simple wound management. Given the high rate of complications and

Antigen specific T-cell responses against tumor antigens are controlled by regulatory T cells in patients with prostate cancer.

Science.gov (United States)

Hadaschik, Boris; Su, Yun; Huter, Eva; Ge, Yingzi; Hohenfellner, Markus; Beckhove, Philipp

2012-04-01

Immunotherapy is a promising approach in an effort to control castration resistant prostate cancer. We characterized tumor antigen reactive T cells in patients with prostate cancer and analyzed the suppression of antitumor responses by regulatory T cells. Peripheral blood samples were collected from 57 patients with histologically confirmed prostate cancer, 8 patients with benign prostatic hyperplasia and 16 healthy donors. Peripheral blood mononuclear cells were isolated and antigen specific interferon-γ secretion of isolated T cells was analyzed by enzyme-linked immunospot assay. T cells were functionally characterized and T-cell responses before and after regulatory T-cell depletion were compared. As test tumor antigens, a panel of 11 long synthetic peptides derived from a total of 8 tumor antigens was used, including prostate specific antigen and prostatic acid phosphatase. In patients with prostate cancer we noted a 74.5% effector T-cell response rate compared with only 25% in patients with benign prostatic hyperplasia and 31% in healthy donors. In most patients 2 or 3 tumor antigens were recognized. Comparing various disease stages there was a clear increase in the immune response against prostate specific antigens from intermediate to high risk tumors and castration resistant disease. Regulatory T-cell depletion led to a significant boost in effector T-cell responses against prostate specific antigen and prostatic acid phosphatase. Tumor specific effector T cells were detected in most patients with prostate cancer, especially those with castration resistant prostate cancer. Since effector T-cell responses against prostate specific antigens strongly increased after regulatory T-cell depletion, our results indicate that immunotherapy efficacy could be enhanced by decreasing regulatory T cells. Copyright © 2012 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Enzalutamide treatment in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy and abiraterone acetate

DEFF Research Database (Denmark)

Thomsen, Frederik Birkebaek; Røder, Martin Andreas; Rathenborg, Per

2014-01-01

OBJECTIVE: The aim of this study was to record prostate-specific antigen (PSA) response and overall survival (OS) for a group of metastatic castration-resistant prostate cancer (mCRPC) patients treated with enzalutamide following progression after abiraterone treatment in the post-chemotherapy se......OBJECTIVE: The aim of this study was to record prostate-specific antigen (PSA) response and overall survival (OS) for a group of metastatic castration-resistant prostate cancer (mCRPC) patients treated with enzalutamide following progression after abiraterone treatment in the post......-chemotherapy setting. MATERIAL AND METHODS: Twenty-four mCRPC patients with progression after abiraterone treatment following primary docetaxel therapy received enzalutamide 160 mg/day. The percentage PSA response was recorded following first line docetaxel, abiraterone and enzalutamide treatment. Fischer's exact test......, Mann-Whitney U test and linear regression model were used to test for differences in PSA response. RESULTS: All patients had a follow-up of at least 3 months. The median PSA response following 1 month of enzalutamide was -12% (range -56% to 76%), while the median best PSA response was -22% (-76% to 76...

Cabazitaxel in patients with metastatic castration-resistant prostate cancer: results of a compassionate use program in the Netherlands

NARCIS (Netherlands)

Wissing, M.D.; Oort, I.M. van; Gerritsen, W.R.; Eertwegh, A.J. van den; Coenen, J.L.; Bergman, A.M.; Gelderblom, H.

2013-01-01

BACKGROUND: Cabazitaxel has been reimbursed as a second-line therapy for patients with metastatic castrate-resistant prostate cancer (mCRPC) in the Netherlands since 2011. Before reimbursement was available, cabazitaxel was provided through a Compassionate Use Program (CUP). We report the results of

Androgen receptor (AR) degradation enhancer ASC-J9® in an FDA-approved formulated solution suppresses castration resistant prostate cancer cell growth.

Science.gov (United States)

Cheng, Max A; Chou, Fu-Ju; Wang, Keliang; Yang, Rachel; Ding, Jie; Zhang, Qiaoxia; Li, Gonghui; Yeh, Shuyuan; Xu, Defeng; Chang, Chawnshang

2018-03-28

ASC-J9 ® is a recently-developed androgen receptor (AR)-degradation enhancer that effectively suppresses castration resistant prostate cancer (PCa) cell proliferation and invasion. The optimal half maximum inhibitory concentrations (IC 50 ) of ASC-J9 ® at various PCa cell confluences (20%, 50%, and 100%) were assessed via both short-term MTT growth assays and long-term clonogenic proliferation assays. Our results indicate that the IC 50 values for ASC-J9 ® increased with increasing cell confluency. The IC 50 values were significantly decreased in PCa AR-positive cells compared to PCa AR-negative cells or in normal prostate cells. This suggests that ASC-J9 ® may function mainly via targeting the AR-positive PCa cells with limited unwanted side-effects to suppress the surrounding normal prostate cells. Mechanism dissection indicated that ASC-J9 ® might function via altering the apoptosis signals to suppress the PCa AR-negative PC-3 cells. Preclinical studies using multiple in vitro PCa cell lines and an in vivo mouse model with xenografted castration-resistant PCa CWR22Rv1 cells demonstrated that ASC-J9 ® has similar AR degradation effects when dissolved in FDA-approved solvents, including DMSO, PEG-400:Tween-80 (95:5), DMA:Labrasol:Tween-80 (10:45:45), and DMA:Labrasol:Tween-20 (10:45:45). Together, results from preclinical studies suggest a potential new therapy with AR-degradation enhancer ASC-J9 ® may potentially be ready to be used in human clinical trials in order to better suppress PCa at later castration resistant stages. Copyright © 2017 Elsevier B.V. All rights reserved.

Transcript Levels of Androgen Receptor Variant 7 and Ubiquitin-Conjugating Enzyme 2C in Hormone Sensitive Prostate Cancer and Castration-Resistant Prostate Cancer.

Science.gov (United States)

Lee, Chan Ho; Ku, Ja Yoon; Ha, Jung Min; Bae, Sun Sik; Lee, Jeong Zoo; Kim, Choung-Soo; Ha, Hong Koo

2017-01-01

This study is designed to identify the androgen receptor variant 7 (AR-V7) status, clinical significance of AR-V7 in hormone sensitive prostate cancer (HSPC). Then, we evaluated AR-V7 and changes of its target gene, ubiquitin-conjugating enzyme E2C (UBE2C) which is an anaphase-promoting complex/cyclosome (APC/C)-specific ubiquitin-conjugating enzyme, in castration-resistant prostate cancer (CRPC) in serial tumor biopsies from patients receiving androgen deprivation therapy. We used RT-PCR and Q-PCR assay to evaluate AR-V7, androgen receptor full length (AR-FL), and UBE2C in tumor biopsies from patients with HSPC and CRPC. We examined associations between mRNA expression of AR-V7 and clinicopathologic factors. Furthermore, to identify other potential genes involved in the development of CRPC, RNA sequencing was conducted, using paired prostate cancer (PCa) tissues obtained immediately prior to treatment and at the time of therapeutic resistance. A total of 13 HSPC patients and three CRPC patients were enrolled. Neither a high Gleason score (score of 8 and 9) nor a high risk of PCa (a high risk of locally advanced PCa according to NCCN guidelines) was correlated with mRNA expression of AR-V7 in HSPC (P = 0.153 and P = 0.215). The mRNA expression of AR-FL, but not AR-V7, was significantly associated with the mRNA expression of UBE2C level in HSPC (P = 0.007). However, increased expression of AR-V7, not AR-FL, paralleled increased expression of UBE2C in the CRPC specimens (P = 0.03). AR-V7 expression status before ADT was likely related to shorter CRPC development in patients treating ADT. The result of the RNA-sequencing analysis using serial samples from the same patient before and after castration demonstrated an increased level of the PI3K regulatory subunit 1 (P = 0.018). Our study revealed the role of UBE2C as a marker of the androgen signaling pathway in PCa. Differential gene expression analysis using serial samples from the same patient

Nuclear-specific AR-V7 Protein Localization is Necessary to Guide Treatment Selection in Metastatic Castration-resistant Prostate Cancer.

Science.gov (United States)

Scher, Howard I; Graf, Ryon P; Schreiber, Nicole A; McLaughlin, Brigit; Lu, David; Louw, Jessica; Danila, Daniel C; Dugan, Lyndsey; Johnson, Ann; Heller, Glenn; Fleisher, Martin; Dittamore, Ryan

2017-06-01

Circulating tumor cells (CTCs) expressing AR-V7 protein localized to the nucleus (nuclear-specific) identify metastatic castration-resistant prostate cancer (mCRPC) patients with improved overall survival (OS) on taxane therapy relative to the androgen receptor signaling inhibitors (ARSi) abiraterone acetate, enzalutamide, and apalutamide. To evaluate if expanding the positivity criteria to include both nuclear and cytoplasmic AR-V7 localization ("nuclear-agnostic") identifies more patients who would benefit from a taxane over an ARSi. The study used a cross-sectional cohort. Between December 2012 and March 2015, 193 pretherapy blood samples, 191 of which were evaluable, were collected and processed from 161 unique mCRPC patients before starting a new line of systemic therapy for disease progression at the Memorial Sloan Kettering Cancer Center. The association between two AR-V7 scoring criteria, post-therapy prostate-specific antigen (PSA) change (PTPC) and OS following ARSi or taxane treatment, was explored. One criterion required nuclear-specific AR-V7 localization, and the other required an AR-V7 signal but was agnostic to protein localization in CTCs. Correlation of AR-V7 status to PTPC and OS was investigated. Relationships with survival were analyzed using multivariable Cox regression and log-rank analyses. A total of 34 (18%) samples were AR-V7-positive using nuclear-specific criteria, and 56 (29%) were AR-V7-positive using nuclear-agnostic criteria. Following ARSi treatment, none of the 16 nuclear-specific AR-V7-positive samples and six of the 32 (19%) nuclear-agnostic AR-V7-positive samples had ≥50% PTPC at 12 weeks. The strongest baseline factor influencing OS was the interaction between the presence of nuclear-specific AR-V7-positive CTCs and treatment with a taxane (hazard ratio 0.24, 95% confidence interval 0.078-0.79; p=0.019). This interaction was not significant when nuclear-agnostic criteria were used. To reliably inform treatment selection

Enzalutamide in Men with Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer: Extended Analysis of the Phase 3 PREVAIL Study

NARCIS (Netherlands)

Beer, T.M.; Armstrong, A.J.; Rathkopf, D.; Loriot, Y.; Sternberg, C.N.; Higano, C.S.; Iversen, P.; Evans, C.P.; Kim, C.S.; Kimura, G.; Miller, K.; Saad, F.; Bjartell, A.S.; Borre, M.; Mulders, P.; Tammela, T.L.; Parli, T.; Sari, S.; Os, S. van; Theeuwes, A.; Tombal, B.

2017-01-01

Enzalutamide significantly improved radiographic progression-free survival (rPFS) and overall survival (OS) among men with chemotherapy-naive metastatic castration-resistant prostate cancer at the prespecified interim analysis of PREVAIL, a phase 3, double-blind, randomized study. We evaluated the

Population-based study on use of chemotherapy in men with castration resistant prostate cancer

OpenAIRE

Lissbrant, Ingela Franck; Garmo, Hans; Widmark, Anders; Stattin, P?r

2013-01-01

Background. Chemotherapy prolongs life and relieves symptoms in men with castration resistant prostate cancer (CRPC). There is limited information on a population level on the use of chemotherapy for CRPC. Material and methods. To assess the use of chemotherapy in men with CRPC we conducted a register-based nationwide population-based study in Prostate Cancer data Base Sweden (PCBaSe) and a nationwide in-patient drug register (SALT database) between May 2009 and December 2010. We assumed that...

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

receptor, castration-resistant prostate cancer, DNA binding domain, androgen response element, AR inhibitor, chromatin, x-ray crystallography , pre-clinical...14228 (months 1-30) 3.2. Synthesis of derivatives of our lead compounds (months 6-30). 3.3.Experimental evaluation of the developed synthetic

Radiation induction of drug resistance in RIF-1 tumors and tumor cells

International Nuclear Information System (INIS)

Hopwood, L.E.; Moulder, J.E.

1989-01-01

The RIF-1 tumor cell line contains a small number of cells (1-20 per 10(6) cells) that are resistant to various single antineoplastic drugs, including 5-fluorouracil (5FU), methotrexate (MTX), and adriamycin (ADR). For 5FU the frequency of drug resistance is lower for tumor-derived cells than for cells from cell culture; for MTX the reverse is true, and for ADR there is no difference. In vitro irradiation at 5 Gy significantly increased the frequency of drug-resistant cells for 5FU, MTX, and ADR. In vivo irradiation at 3 Gy significantly increased the frequency of drug-resistant cells for 5FU and MTX, but not for ADR. The absolute risk for in vitro induction of MTX, 5FU, and ADR resistance, and for in vivo induction of 5FU resistance, was 1-3 per 10(6) cells per Gy; but the absolute risk for in vivo induction of MTX resistance was 54 per 10(6) cells per Gy. The frequency of drug-resistant cells among individual untreated tumors was highly variable; among individual irradiated tumors the frequency of drug-resistant cells was significantly less variable. These studies provide supporting data for models of the development of tumor drug resistance, and imply that some of the drug resistance seen when chemotherapy follows radiotherapy may be due to radiation-induced drug resistance

Targeting Hsp27/eIF4E interaction with phenazine compound: a promising alternative for castration-resistant prostate cancer treatment.

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Hajer, Ziouziou; Claudia, Andrieu; Erik, Laurini; Sara, Karaki; Maurizio, Fermeglia; Ridha, Oueslati; David, Taieb; Michel, Camplo; Olivier, Siri; Sabrina, Pricl; Maria, Katsogiannou; Palma, Rocchi

2017-09-29

The actual strategy to improve current therapies in advanced prostate cancer involves targeting genes activated by androgen withdrawal, either to delay or prevent the emergence of the castration-refractory phenotype. However, these genes are often implicated in several physiological processes, and long-term inhibition of survival proteins might be accompanied with cytotoxic effects. To avoid this problem, an alternative therapeutic strategy relies on the identification and use of compounds that disrupt specific protein-protein interactions involved in androgen withdrawal. Specifically, the interaction of the chaperone protein Hsp27 with the initiation factor eIF4E leads to the protection of protein synthesis initiation process and enhances cell survival during cell stress induced by castration or chemotherapy. Thus, in this work we aimed at i) identifying the interaction site of the Hsp27/eIF4E complex and ii) interfere with the relevant protein/protein association mechanism involved in castration-resistant progression of prostate cancer. By a combination of experimental and modeling techniques, we proved that eIF4E interacts with the C-terminal part of Hsp27, preferentially when Hsp27 is phosphorylated. We also observed that the loss of this interaction increased cell chemo-and hormone-sensitivity. In order to find a potential inhibitor of Hsp27/eIF4E interaction, BRET assays in combination with molecular simulations identified the phenazine derivative 14 as the compound able to efficiently interfere with this protein/protein interaction, thereby inhibiting cell viability and increasing cell death in chemo- and castration-resistant prostate cancer models in vitro and in vivo .

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.

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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.

Study the Origin and Mechanisms of Castration Resistance Characterized by Outgrowth of Prostate Cancer Cells with Low/Negative Androgen Receptor

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2017-12-01

Prostate Cancer Cells with Low/Negative Androgen Receptor 5b. GRANT NUMBER W81XWH-15-1-0540 5c. PROGRAM...role of androgen receptor (AR) signaling in disease progression, the current approach to treat prostate cancer is AR-targeted therapy. While this... Prostate cancer ; Androgen receptor ; Castration-resistant prostate cancer (CRPC); Enzalutamide resistance; GREB1; p300 6 Accomplishments Specific

Epigenetic Machinery Regulates Alternative Splicing of Androgen Receptor (AR) Gene in Castration-Resistant Prostate Cancer (CRPC)

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2017-09-01

Splicing of Androgen Receptor (AR) Gene in Castration-Resistant Prostate Cancer (CRPC) 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Jer...Epigenetic regulation of androgen receptor signaling in prostate cancer . Epigenetics. 5, 100-104. 2. Duan LL, Rai G , Roggero C, Zhang Q-J, Wei Q... Prostate Cancer (CRPC) PRINCIPAL INVESTIGATOR: Hsieh, Jer-Tsong CONTRACTING ORGANIZATION: University of Texas Southwestern Medical Center

Patient-derived Hormone-naive Prostate Cancer Xenograft Models Reveal Growth Factor Receptor Bound Protein 10 as an Androgen Receptor-repressed Gene Driving the Development of Castration-resistant Prostate Cancer.

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Hao, Jun; Ci, Xinpei; Xue, Hui; Wu, Rebecca; Dong, Xin; Choi, Stephen Yiu Chuen; He, Haiqing; Wang, Yu; Zhang, Fang; Qu, Sifeng; Zhang, Fan; Haegert, Anne M; Gout, Peter W; Zoubeidi, Amina; Collins, Colin; Gleave, Martin E; Lin, Dong; Wang, Yuzhuo

2018-06-01

Although androgen deprivation therapy is initially effective in controlling growth of hormone-naive prostate cancers (HNPCs) in patients, currently incurable castration-resistant prostate cancer (CRPC) inevitably develops. To identify CRPC driver genes that may provide new targets to enhance CRPC therapy. Patient-derived xenografts (PDXs) of HNPCs that develop CRPC following host castration were examined for changes in expression of genes at various time points after castration using transcriptome profiling analysis; particular attention was given to pre-CRPC changes in expression indicative of genes acting as potential CRPC drivers. The functionality of a potential CRPC driver was validated via its knockdown in cultured prostate cancer cells; its clinical relevance was established using data from prostate cancer patient databases. Eighty genes were found to be significantly upregulated at the CRPC stage, while seven of them also showed elevated expression prior to CRPC development. Among the latter, growth factor receptor bound protein 10 (GRB10) was the most significantly and consistently upregulated gene. Moreover, elevated GRB10 expression in clinical prostate cancer samples correlated with more aggressive tumor types and poorer patient treatment outcome. GRB10 knockdown markedly reduced prostate cancer cell proliferation and activity of AKT, a well-established CRPC mediator. A positive correlation between AKT activity and GRB10 expression was also found in clinical cohorts. GRB10 acts as a driver of CRPC and sensitizes androgen receptor pathway inhibitors, and hence GRB10 targeting provides a novel therapeutic strategy for the disease. Development of castration-resistant prostate cancer (CRPC) is a major problem in the management of the disease. Using state-of-the-art patient-derived hormone-naive prostate cancer xenograft models, we found and validated the growth factor receptor bound protein 10 gene as a driver of CRPC, indicating that it may be used as a

A passion for castration: characterizing men who are fascinated with castration, but have not been castrated.

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Roberts, Lesley F; Brett, Michelle A; Johnson, Thomas W; Wassersug, Richard J

2008-07-01

A number of men have extreme castration ideations. Many only fantasize about castration; others actualize their fantasies. We wish to identify factors that distinguish those who merely fantasize about being castrated from those who are at the greatest risk of genital mutilation. Seven hundred thirty-one individuals, who were not castrated, responded to a survey posted on http://www.eunuch.org. We compared the responses of these "wannabes" to those of 92 men who were voluntarily castrated and responded to a companion survey. Main Outcome Measures. Respondents answered the questionnaire items relating to demographics, origin of interest in castration, and ambition toward eunuchdom. Two categories of wannabes emerged. A large proportion ( approximately 40%) of wannabes' interest in castration was singularly of a fetishistic nature, and these men appeared to be at a relatively low risk of irreversible genital mutilation. Approximately 20% of the men, however, appeared to be at great risk of genital mutilation. They showed a greater desire to reduce libido, change their genital appearance, transition out of male, and prevent sexually offensive behavior. Nineteen percent of all wannabes have attempted self-castration, yet only 10% have sought medical assistance. We identify several motivating factors for extreme castration ideations and provide a classification for reasons why some males desire orchiectomies. Castration ideations fall under several categories of the Diagnostic and Statistical Manual of Mental Disorders, 4th Ed. (DSM-IV), most notably a Gender Identity Disorder other than male-to-female (MtF) transsexual (i.e., male-to-eunuch) and a Body Identity Integrity Disorder. Physicians need to be aware of males who have strong desires for emasculation without a traditional MtF transsexual identity.

Histone 2B-GFP Label-Retaining Prostate Luminal Cells Possess Progenitor Cell Properties and Are Intrinsically Resistant to Castration

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Dingxiao Zhang

2018-01-01

Full Text Available The existence of slow-cycling luminal cells in the prostate has been suggested, but their identity and functional properties remain unknown. Using a bigenic mouse model to earmark, isolate, and characterize the quiescent stem-like cells, we identify a label-retaining cell (LRC population in the luminal cell layer as luminal progenitors. Molecular and biological characterizations show that these luminal LRCs are significantly enriched in the mouse proximal prostate, exhibit relative dormancy, display bipotency in both in vitro and in vivo assays, and express a stem/progenitor gene signature with resemblance to aggressive prostate cancer. Importantly, these LRCs, compared with bulk luminal cells, maintain a lower level of androgen receptor (AR expression and are less androgen dependent and also castration resistant in vivo. Finally, analysis of phenotypic markers reveals heterogeneity within the luminal progenitor cell pool. Our study establishes luminal LRCs as progenitors that may serve as a cellular origin for castration-resistant prostate cancer.

The retinamide VNLG-152 inhibits f-AR/AR-V7 and MNK-eIF4E signaling pathways to suppress EMT and castration-resistant prostate cancer xenograft growth.

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Ramamurthy, Vidya P; Ramalingam, Senthilmurugan; Gediya, Lalji K; Njar, Vincent C O

2018-03-01

VNLG-152 is a novel retinamide (NR) shown to suppress growth and progression of genetically diverse prostate cancer cells via inhibition of androgen receptor signaling and eukaryotic initiation factor 4E (eIF4E) translational machinery. Herein, we report therapeutic effects of VNLG-152 on castration-resistant prostate cancer (CRPC) growth and metastatic phenotype in a CRPC tumor xenograft model. Administration of VNLG-152 significantly and dose-dependently suppressed the growth of aggressive CWR22Rv1 tumors by 63.4% and 76.3% at 10 and 20 mg·kg -1 bw, respectively (P AR)/androgen receptor splice variant-7 (AR-V7), mitogen-activated protein kinase-interacting kinases 1 and 2 (MNK1/2), phosphorylated eIF4E and their associated target proteins, including prostate-specific antigen, cyclin D1 and Bcl-2, were strongly decreased in VNLG-152-treated tumors signifying inhibition of f-AR/AR-V7 and MNK-eIF4E signaling in VNLG-152-treated CWR22Rv1 tumors as observed in vitro. VNLG-152 also suppressed the epithelial to mesenchymal transition in CWR22Rv1 tumors as evidenced by repression of N-cadherin, β-catenin, claudin, Slug, Snail, Twist, vimentin and matrix metalloproteinases (MMP-2 and MMP-9) with upsurge in E-cadherin. These results highlight the promising use of VNLG-152 in CRPC therapy and justify its further development towards clinical trials. © 2018 Federation of European Biochemical Societies.

Docetaxel chemotherapy in metastatic castration-resistant prostate cancer: cost of care in Medicare and commercial populations.

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Armstrong, A; Bui, C; Fitch, K; Sawhney, T Goss; Brown, B; Flanders, S; Balk, M; Deangelis, J; Chambers, J

2017-06-01

To estimate the healthcare costs and characteristics of docetaxel chemotherapy episodes of care for men with metastatic castration-resistant prostate cancer (mCRPC). This study used the Medicare 5% sample and MarketScan Commercial (2010-2013) claims data sets to identify men with mCRPC and initial episodes of docetaxel treatment. Docetaxel episodes included docetaxel claim costs from the first claim until 30 days after the last claim, with earlier termination for death, insurance disenrollment, or the end of a 24-month look-forward period from initial docetaxel index date. Docetaxel drug claim costs were adjusted for 2011 generic docetaxel introduction, while other costs were adjusted to 2015 values using the national average annual unit cost increase. This study identified 281 Medicare-insured and 155 commercially insured men, with 325 and 172 docetaxel episodes, respectively. The average number of cycles (unique docetaxel infusion days) per episode was 6.9 for Medicare and 6.3 for commercial cohorts. The average cost per episode was $28,792 for Medicare and $67,958 for commercial cohorts, with docetaxel drug costs contributing $2,588 and $13,169 per episode, respectively. The average cost per episode on docetaxel infusion days was $8,577 (30%) for Medicare and $28,412 (42%) for commercial. Non-docetaxel infusion day costs included $7,074 (25%) for infused or injected drugs for Medicare, $10,838 (16%) for commercial cohorts, and $6,875 (24%) and $9,324 (14%) for inpatient admissions, respectively. The applicability is only to the metastatic castration-resistance clinical setting, rather than the metastatic hormone-sensitive setting, and the lack of data on the cost effectiveness of different sequencing strategies of a range of systemic therapies including enzalutamide, abiraterone, radium-223, and taxane chemotherapy. The majority of docetaxel episode costs in Medicare and commercial mCRPC populations were non-docetaxel drug costs. Future research should evaluate

Cotargeting of Androgen Synthesis and Androgen Receptor Expression as a Novel Treatment for Castration Resistant Prostate Cancer

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2017-08-01

disease [2-4]. The major mechanism underlying the development of CRPC is the reactivation of the androgen receptor (AR), the driver of prostate cancer ...Epigenetic Activator of Androgen Receptor Expression in Castration- Resistant Prostate Cancer . Indiana Basic Urological Research (IBUR) Symposium...principal discipline(s) of the project? Androgen receptor (AR) is the driver of prostate cancer development and progression and is the validated

Randomized, Placebo-Controlled, Phase III Trial of Sunitinib Plus Prednisone Versus Prednisone Alone in Progressive, Metastatic, Castration-Resistant Prostate Cancer

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Michaelson, M Dror; Oudard, Stephane; Ou, Yen-Chuan

2014-01-01

PURPOSE: We evaluated angiogenesis-targeted sunitinib therapy in a randomized, double-blind trial of metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: Men with progressive mCRPC after docetaxel-based chemotherapy were randomly assigned 2:1 to receive sunitinib 37.5 mg...

Imaging response during therapy with radium-223 for castration-resistant prostate cancer with bone metastases

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Keizman, D; Fosboel, M O; Reichegger, H

2017-01-01

BACKGROUND: The imaging response to radium-223 therapy is at present poorly described. We aimed to describe the imaging response to radium-223 treatment. METHODS: We retrospectively evaluated the computed tomography (CT) and bone scintigraphy response of metastatic castration-resistant prostate c....../or radiological) may be noted during the first 3 months, and should not be confused with progression. Imaging by CT scan should be considered after three and six doses of radium-223 to rule out extraskeletal disease progression....

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

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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.

Combination treatment with docetaxel and histone deacetylase inhibitors downregulates androgen receptor signaling in castration-resistant prostate cancer.

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Park, Sang Eun; Kim, Ha-Gyeong; Kim, Dong Eun; Jung, Yoo Jung; Kim, Yunlim; Jeong, Seong-Yun; Choi, Eun Kyung; Hwang, Jung Jin; Kim, Choung-Soo

2018-04-01

Backgrounds Since most patients with castration-resistant prostate cancer (CRPC) develop resistance to its standard therapy docetaxel, many studies have attempted to identify novel combination treatment to meet the large clinical unmet need. In this study, we examined whether histone deacetylase inhibitors (HDACIs) enhanced the effect of docetaxel on AR signaling in CRPC cells harboring AR and its splice variants. Methods HDACIs (vorinostat and CG200745) were tested for their ability to enhance the effects of docetaxel on cell viability and inhibition of AR signaling in CRPC 22Rv1 and VCaP cells by using CellTiter-Glo™ Luminescent cell viability assay, synergy index analysis and Western blotting. The nuclear localization of AR was examined via immunocytochemical staining in 22Rv1 cells and primary tumor cells from a patient with CRPC. Results Combination treatment with HDACIs (vorinostat or CG200745) and docetaxel synergistically inhibited the growth of 22Rv1 and VCaP cells. Consistently, the combination treatment decreased the levels of full-length AR (AR-FL), AR splice variants (AR-Vs), prostate-specific antigen (PSA), and anti-apoptotic Bcl-2 proteins more efficiently compared with docetaxel or vorinostat alone. Moreover, the combination treatment accelerated the acetylation and bundling of tubulin, which significantly inhibited the nuclear accumulation of AR in 22Rv1 cells. The cytoplasmic colocalization of AR-FL and AR-V7 with microtubule bundles increased after combination treatment in primary tumor cells from a patient with CRPC. Conclusions The results suggested that docetaxel, in combination with HDACIs, suppressed the expression and nuclear translocation of AR-FL and AR-Vs and showed synergistic anti-proliferative effect in CRPC cells. This combination therapy may be useful for the treatment of patients with CRPC.

Abiraterone Acetate: A Review in Metastatic Castration-Resistant Prostrate Cancer.

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Scott, Lesley J

2017-09-01

Oral abiraterone acetate (Zytiga ® ) is a selective inhibitor of CYP17 and thereby inhibits androgen biosynthesis, with androgen signalling crucial in the progression from primary to metastatic prostate cancer (PC) and subsequently, in the development of metastatic castration-resistant PC (mCRPC). In large phase 3 trials and in the clinical practice setting, oral abiraterone acetate in combination with prednisone was an effective treatment and had an acceptable, manageable tolerability and safety profile in chemotherapy-naive and docetaxel-experienced men with mCRPC. In the pivotal global phase 3 trials, relative to placebo (+prednisone), abiraterone acetate (+prednisone) prolonged overall survival (OS) at data maturity (final analysis) and radiographic progression-free survival (rPFS) at all assessed timepoints. Given its efficacy in prolonging OS and its convenient once-daily oral regimen, in combination with prednisone, abiraterone acetate is an important first-line option for the treatment of mCRPC.

Progression of metastatic castrate-resistant prostate cancer: impact of therapeutic intervention in the post-docetaxel space

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Sartor A Oliver

2011-04-01

Full Text Available Abstract Despite the proven success of hormonal therapy for prostate cancer using chemical or surgical castration, most patients eventually will progress to a phase of the disease that is metastatic and shows resistance to further hormonal manipulation. This has been termed metastatic castrate-resistant prostate cancer (mCRPC. Despite this designation, however, there is evidence that androgen receptor (AR-mediated signaling and gene expression can persist in mCRPC, even in the face of castrate levels of androgen. This may be due in part to the upregulation of enzymes involved in androgen synthesis, the overexpression of AR, or the emergence of mutant ARs with promiscuous recognition of various steroidal ligands. The therapeutic options were limited and palliative in nature until trials in 2004 demonstrated that docetaxel chemotherapy could significantly improve survival. These results established first-line docetaxel as the standard of care for mCRPC. After resistance to further docetaxel therapy develops, treatment options were once again limited. Recently reported results from phase 3 trials have shown that additional therapy with the novel taxane cabazitaxel (with prednisone, or treatment with the antiandrogen abiraterone (with prednisone could improve survival for patients with mCRPC following docetaxel therapy. Compared with mitoxantrone/prednisone, cabazitaxel/prednisone significantly improved overall survival, with a 30% reduction in rate of death, in patients with progression of mCRPC after docetaxel therapy in the TROPIC trial. Similarly, abiraterone acetate (an inhibitor of androgen biosynthesis plus prednisone significantly decreased the rate of death by 35% compared with placebo plus prednisone in mCRPC patients progressing after prior docetaxel therapy in the COU-AA-301 trial. Results of these trials have thus established two additional treatment options for mCRPC patients in the "post-docetaxel space." In view of the continued AR

Challenges to improved therapeutics for metastatic castrate resistant prostate cancer: from recent successes and failures

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Huang Xuan

2012-07-01

Full Text Available Abstract Men with metastatic castration-resistant prostate cancer (mCRPC carry poor prognosis despite the use of docetaxel-based regimens which has modest survival benefit shown by randomized clinical trials. Significant progress in the discovery of novel therapeutic agents has been made in the past few years. While sipuleucel-T, cabazitaxel, and abiraterone gained regulatory approval in 2010 and 2011, several highly promising candidates/regimens have failed in large scale clinical trials. Challenges remain to optimize the design and interpretation of clinical trial results and develop more effective strategies for mCRPC. In this review, we examined the positive and negative clinical trials in mCRPC in the past and discussed the various aspects of clinical trial design including selection of targets and appropriate outcome measures, biomarker development and implementation, and strategies for combination therapy.

Further analysis of PREVAIL: enzalutamide use in chemotherapy-naïve men with metastatic castration-resistant prostate cancer.

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Aragon-Ching, Jeanny B

2014-01-01

PREVAIL was a phase III multinational, double-blind, placebo-controlled trial that enrolled chemotherapy-naïve men with metastatic castration-resistant prostate cancer (mCRPC), which showed remarkable improvement in co-primary endpoints with an overall 81% reduction in the risk of radiographic progression, as well as 29% reduction in the risk of death in favor of the enzalutamide arm over placebo. All secondary endpoints including time to subsequent chemotherapy initiation and prostate specific antigen (PSA) progression were in favor of the enzalutamide arm. The results of PREVAIL shows the utility of enzalutamide that would likely soon expand the indication to asymptomatic or minimally symptomatic men with mCRPC not previously treated with chemotherapy.

Novel agents in the management of castration resistant prostate cancer

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Shruti Chaturvedi

2014-01-01

Full Text Available Prostate cancer (PCa is a leading cause of cancer mortality in men and despite high cure rates with surgery and/or radiation, 30-40% of patients will eventually develop advanced disease. Androgen deprivation is the first line therapy for standard of care for men with advanced disease. Eventually however all men will progress to castration-resistant prostate cancer (CRPC. Insight into the molecular mechanisms of androgen resistance has led to the development of alternative novel hormonal agents. Newer hormonal agents such as abiraterone, enzalutamide and TOK-001; and the first cancer vaccine, Sipuleucel T have been approved for use in men with CRPC. The recognition of the importance of bone health and morbidity associated with skeletal related events has led to the introduction of the receptor activator of nuclear factor kappa-B-ligand inhibitor denosumab. Other molecularly targeted therapies have shown promise in pre-clinical studies, but this has not consistently translated into clinical efficacy. It is increasingly evident that CRPC is a heterogeneous disease and an individualized approach directed at identifying primary involvement of specific pathways could maximize the benefit from targeted therapies. This review focuses on targeted therapy for PCa with special emphasis on therapies that have been Food and Drug Administration approved for use in men with CRPC.

Orphan nuclear receptor TLX contributes to androgen insensitivity in castration-resistant prostate cancer via its repression of androgen receptor transcription.

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Jia, Lin; Wu, Dinglan; Wang, Yuliang; You, Wenxing; Wang, Zhu; Xiao, Lijia; Cai, Ganhui; Xu, Zhenyu; Zou, Chang; Wang, Fei; Teoh, Jeremy Yuen-Chun; Ng, Chi-Fai; Yu, Shan; Chan, Franky L

2018-03-20

The metastatic castration-resistant prostate cancer (CRPC) is a lethal form of prostate cancer, in which the expression of androgen receptor (AR) is highly heterogeneous. Indeed, lower AR expression and attenuated AR signature activity is shown in CRPC tissues, especially in the subset of neuroendocrine prostate cancer (NEPC) and prostate cancer stem-like cells (PCSCs). However, the significance of AR downregulation in androgen insensitivity and de-differentiation of tumor cells in CRPC is poorly understood and much neglected. Our previous study shows that the orphan nuclear receptor TLX (NR2E1), which is upregulated in prostate cancer, plays an oncogenic role in prostate carcinogenesis by suppressing oncogene-induced senescence. In the present study, we further established that TLX exhibited an increased expression in metastatic CRPC. Further analyses showed that overexpression of TLX could confer resistance to androgen deprivation and anti-androgen in androgen-dependent prostate cancer cells in vitro and in vivo, whereas knockdown of endogenous TLX could potentiate the sensitivity to androgen deprivation and anti-androgen in prostate cancer cells. Our study revealed that the TLX-induced resistance to androgen deprivation and anti-androgen was mediated through its direct suppression of AR gene transcription and signaling in both androgen-stimulated and -unstimulated prostate cancer cells. We also characterized that TLX could bind directly to AR promoter and repress AR transcription by recruitment of histone modifiers, including HDAC1, HDAC3, and LSD1. Together, our present study shows, for the first time, that TLX can contribute to androgen insensitivity in CRPC via repression of AR gene transcription and signaling, and also implicates that targeting the druggable TLX may have a potential therapeutic significance in CRPC management, particularly in NEPC and PCSCs.

AR-V7 in Peripheral Whole Blood of Patients with Castration-resistant Prostate Cancer: Association with Treatment-specific Outcome Under Abiraterone and Enzalutamide.

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Seitz, Anna Katharina; Thoene, Silvia; Bietenbeck, Andreas; Nawroth, Roman; Tauber, Robert; Thalgott, Mark; Schmid, Sebastian; Secci, Ramona; Retz, Margitta; Gschwend, Jürgen E; Ruland, Jürgen; Winter, Christof; Heck, Matthias M

2017-11-01

It has been demonstrated that androgen receptor splice variant 7 (AR-V7) expression in circulating tumor cells (CTCs) predicts poor treatment response in metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone or enzalutamide. To develop a practical and robust liquid profiling approach for direct quantification of AR-V7 in peripheral whole blood without the need for CTC capture and to determine its potential for predicting treatment response in mCRPC patients. Whole blood samples from a prospective biorepository of 85 mCRPC patients before treatment initiation with abiraterone (n=56) or enzalutamide (n=29) were analyzed via droplet digital polymerase chain reaction. The association of AR-V7 status with prostate-specific antigen (PSA) response defined by PSA decline ≥50% and with PSA-progression-free survival (PSA-PFS), clinical PFS, and overall survival (OS) was assessed. High AR-V7 expression levels in whole blood were detectable in 18% (15/85) of patients. No patient with high AR-V7 expression achieved a PSA response, and AR-V7 status was an independent predictor of PSA response in multivariable logistic regression analysis (p=0.03). High AR-V7 expression was associated with shorter PSA-PFS (median 2.4 vs 3.7 mo; pAR-V7 expression remained an independent predictor of shorter PSA-PFS (hazard ratio [HR] 7.0, 95% confidence interval [CI] 2.3-20.7; pAR-V7 mRNA levels in whole blood is a simple and promising approach to predict poor treatment outcome in mCRPC patients receiving abiraterone or enzalutamide. We established a method for determining AR-V7 status in whole blood. This test predicted treatment resistance in patients with metastatic castration-resistant prostate cancer undergoing treatment with abiraterone or enzalutamide. Prospective validation is needed before application to clinical practice. Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Understanding and Targeting Tumor Microenvironment in Prostate Cancer to Inhibit Tumor Progression and Castration Resistance

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2016-10-01

cancer-secreted chemokine to attract Cxcr2-expressing MDSCs and, correspondingly, pharmacological inhibition of Cxcr2 impeded tumor progression...impact of pharmacological inhibition of Cxcl5 and Cxcr2 on MDSCs using the transwell migration assay 26 . First, anti-Cxcl5 neutralizing antibody...and MRI . (B) Generation of the CPPSML chimera model. (C) Fluorescence microscopy and H&E image of snap frozen prostate tumor from chimera showing that

The Interactions between Insulin and Androgens in Progression to Castrate-Resistant Prostate Cancer

Directory of Open Access Journals (Sweden)

Jennifer H. Gunter

2012-01-01

Full Text Available An association between the metabolic syndrome and reduced testosterone levels has been identified, and a specific inverse relationship between insulin and testosterone levels suggests that an important metabolic crosstalk exists between these two hormonal axes; however, the mechanisms by which insulin and androgens may be reciprocally regulated are not well described. Androgen-dependant gene pathways regulate the growth and maintenance of both normal and malignant prostate tissue, and androgen-deprivation therapy (ADT in patients exploits this dependence when used to treat recurrent and metastatic prostate cancer resulting in tumour regression. A major systemic side effect of ADT includes induction of key features of the metabolic syndrome and the consistent feature of hyperinsulinaemia. Recent studies have specifically identified a correlation between elevated insulin and high-grade PCa and more rapid progression to castrate resistant disease. This paper examines the relationship between insulin and androgens in the context of prostate cancer progression. Prostate cancer patients present a promising cohort for the exploration of insulin stabilising agents as adjunct treatments for hormone deprivation or enhancers of chemosensitivity for treatment of advanced prostate cancer.

The Interactions between Insulin and Androgens in Progression to Castrate-Resistant Prostate Cancer

Science.gov (United States)

Gunter, Jennifer H.; Lubik, Amy A.; McKenzie, Ian; Pollak, Michael; Nelson, Colleen C.

2012-01-01

An association between the metabolic syndrome and reduced testosterone levels has been identified, and a specific inverse relationship between insulin and testosterone levels suggests that an important metabolic crosstalk exists between these two hormonal axes; however, the mechanisms by which insulin and androgens may be reciprocally regulated are not well described. Androgen-dependant gene pathways regulate the growth and maintenance of both normal and malignant prostate tissue, and androgen-deprivation therapy (ADT) in patients exploits this dependence when used to treat recurrent and metastatic prostate cancer resulting in tumour regression. A major systemic side effect of ADT includes induction of key features of the metabolic syndrome and the consistent feature of hyperinsulinaemia. Recent studies have specifically identified a correlation between elevated insulin and high-grade PCa and more rapid progression to castrate resistant disease. This paper examines the relationship between insulin and androgens in the context of prostate cancer progression. Prostate cancer patients present a promising cohort for the exploration of insulin stabilising agents as adjunct treatments for hormone deprivation or enhancers of chemosensitivity for treatment of advanced prostate cancer. PMID:22548055

Prognostic factors and risk stratification in patients with castration-resistant prostate cancer receiving docetaxel-based chemotherapy.

Science.gov (United States)

Yamashita, Shimpei; Kohjimoto, Yasuo; Iguchi, Takashi; Koike, Hiroyuki; Kusumoto, Hiroki; Iba, Akinori; Kikkawa, Kazuro; Kodama, Yoshiki; Matsumura, Nagahide; Hara, Isao

2016-03-22

While novel drugs have been developed, docetaxel remains one of the standard initial systemic therapies for castration-resistant prostate cancer (CRPC) patients. Despite the excellent anti-tumor effect of docetaxel, its severe adverse effects sometimes distress patients. Therefore, it would be very helpful to predict the efficacy of docetaxel before treatment. The aims of this study were to evaluate the potential value of patient characteristics in predicting overall survival (OS) and to develop a risk classification for CRPC patients treated with docetaxel-based chemotherapy. This study included 79 patients with CRPC treated with docetaxel. The variables, including patient characteristics at diagnosis and at the start of chemotherapy, were retrospectively collected. Prognostic factors predicting OS were analyzed using the Cox proportional hazard model. Risk stratification for overall survival was determined based on the results of multivariate analysis. PSA response ≥50 % was observed in 55 (69.6 %) of all patients, and the median OS was 22.5 months. The multivariate analysis showed that age, serum PSA level at the start of chemotherapy, and Hb were independent prognostic factors for OS. In addition, ECOG performance status (PS) and the CRP-to-albumin ratio were not significant but were considered possible predictors for OS. Risk stratification according to the number of these risk factors could effectively stratify CRPC patients treated with docetaxel in terms of OS. Age, serum PSA level at the start of chemotherapy, and Hb were identified as independent prognostic factors of OS. ECOG PS and the CRP-to-albumin ratio were not significant, but were considered possible predictors for OS in Japanese CRPC patients treated with docetaxel. Risk stratification based on these factors could be helpful for estimating overall survival.

Can palliative radiotherapy influence prostate-specific antigen response in patients with castrate-resistant prostate cancer treated with systemic therapy (chemotherapy or abiraterone)?—a report of three cases

International Nuclear Information System (INIS)

Hingorani, Mohan; Dixit, Sanjay; Pugazhenthi, Pattu; Hawkyard, Simon; Robertson, Andrew; Khafagy, Richard

2015-01-01

Palliative radiotherapy (pRT) is primarily employed for palliation of bone pain in patients with castrate-resistant prostate cancer (CRPC). However, evidence that pRT influences prostate-specific antigen response in patients with CRPC on systemic therapy is lacking. We describe three cases of CRPC progressing after treatment with docetaxel (n=2) and abiraterone (n=1), who responded unusually after pRT for bone pain with the development of a significant biochemical response and restoration of response to systemic therapy. The possibility of pRT influencing metastatic disease in CRPC has not been previously reported, and raises the possibility of radiation-induced modulation of anti-tumor immune response mechanisms that may play a role in the restoration of response to systemic treatment

AR-V7 in circulating tumor cells cluster as a predictive biomarker of abiraterone acetate and enzalutamide treatment in castration-resistant prostate cancer patients.

Science.gov (United States)

Okegawa, Takatsugu; Ninomiya, Naoki; Masuda, Kazuki; Nakamura, Yu; Tambo, Mitsuhiro; Nutahara, Kikuo

2018-06-01

We examined whether androgen receptor splice variant 7 (AR-V7) in circulating tumor cell(CTC)clusters can be used to predict survival in patients with bone metastatic castration resistant-prostate cancer (mCRPC) treated with abiraterone or enzalutamide. We retrospectively enrolled 98 patients with CRPC on abiraterone or enzalutamide, and investigated the prognostic value of CTC cluster detection (+ v -) and AR-V7 detection (+ v -) using a CTC cluster detection - based AR-V7 mRNA assay. We examined ≤50% prostate-specific antigen (PSA) responses, PSA progression-free survival (PSA-PFS), clinical and radiological progression-free survival (radiologic PSF), and overall survival (OS). We then assessed whether AR-V7 expression in CTC clusters identified after On-chip multi-imaging flow cytometry was related to disease progression and survival after first-line systemic therapy. All abiraterone-treated or enzalutamide-treated patients received prior docetaxel. The median follow-up was 20.7 (range: 3.0-37.0) months in the abiraterone and enzalutamide cohorts, respectively. Forty-nine of the 98 men (50.0%) were CTC cluster (-), 23 of the 98 men (23.5%) were CTC cluster(+)/AR-V7(-), and 26 of the 98 men (26.5%) were CTC cluster(+)/AR-V7(+). CTC cluster(+)/AR-V7(+) patients were more likely to have EOD ≥3 at diagnosis (P = 0.003), pain (P = 0.023), higher alkaline phosphatase levels (P cluster(+), CTC cluster(+)/AR-V7(-), and ALP >UNL were independently associated with a poor PSA-PFS, radiographic PFS, and OS in abiraterone-treated patients and enzalutamide-treated patients. The CTC clusters and AR-V7-positive CTC clusters detected were important for assessing the response to abiraterone or enzalutamide therapy and for predicting disease outcome. © 2018 Wiley Periodicals, Inc.

Clinical activity and tolerability of enzalutamide (MDV3100) in patients with metastatic, castration-resistant prostate cancer who progress after docetaxel and abiraterone treatment

NARCIS (Netherlands)

Badrising, S.; Noort, V van; Oort, I.M. van; Berg, H.P. van den; Los, M.; Hamberg, P.; Coenen, J.L.; Eertwegh, A.J. van den; Jong, I.J. de; Kerver, E.D.; Tinteren, H. van; Bergman, A.M.

2014-01-01

BACKGROUND: Enzalutamide (Enz) and abiraterone acetate (AA) are hormone treatments that have a proven survival advantage in patients with metastatic, castration-resistant prostate cancer who previously received docetaxel (Doc). Recently, limited activity of AA after Enz and of Enz after AA was

Randomized, Double-Blind, Phase III Trial of Ipilimumab Versus Placebo in Asymptomatic or Minimally Symptomatic Patients With Metastatic Chemotherapy-Naive Castration-Resistant Prostate Cancer

DEFF Research Database (Denmark)

Beer, Tomasz M; Kwon, Eugene D; Drake, Charles G

2017-01-01

Purpose Ipilimumab increases antitumor T-cell responses by binding to cytotoxic T-lymphocyte antigen 4. We evaluated treatment with ipilimumab in asymptomatic or minimally symptomatic patients with chemotherapy-naive metastatic castration-resistant prostate cancer without visceral metastases. Pat...

Prostate-specific Antigen Decline After 4 Weeks of Treatment with Abiraterone Acetate and Overall Survival in Patients with Metastatic Castration-resistant Prostate Cancer

NARCIS (Netherlands)

Rescigno, P.; Lorente, D.; Bianchini, D.; Ferraldeschi, R.; Kolinsky, M.P.; Sideris, S.; Zafeiriou, Z.; Sumanasuriya, S.; Smith, A.D.; Mehra, N.; Jayaram, A.; Perez-Lopez, R.; Mateo, J.; Parker, C.; Dearnaley, D.P.; Tunariu, N.; Reid, A.; Attard, G.; Bono, J.S. de

2016-01-01

BACKGROUND: The availability of multiple new treatments for metastatic castration-resistant prostate cancer (mCRPC) mandates earlier treatment switches in the absence of a response. A decline in prostate-specific antigen (PSA) is widely used to monitor treatment response, but is not validated as an

Radium-223-Dichloride in Castration Resistant Metastatic Prostate Cancer—Preliminary Results of the Response Evaluation Using F-18-Fluoride PET/CT

Directory of Open Access Journals (Sweden)

Kalevi Kairemo

2015-10-01

Full Text Available The purpose of this study was to evaluate the outcome after Radium-223-dichloride (223RaCl2 treatment of patients with skeletal metastases of castration resistant prostate cancer using whole-body 18F-Fluoride PET/CT. Sodium 18F-fluoride [18F]-NaF PET/CT was performed prior the treatment of 223RaCl2, after the first cycle and after the sixth cycle. The skeletal metastases were analyzed quantitatively using modified PET response evaluation PERCIST criteria. The patients were also analyzed for S-PSA. All ten patients responded in [18F]-NaF scans after 6 cycles, but interim analysis after the 1st cycle did not give additional information about the outcome. The S-PSA decrease correlated with [18F]-NaF response, only 1 patient demonstrated progressive disease, i.e., >25% increase in S-PSA values during 223RaCl2. Our results (although preliminary suggest that 18F-Fluoride PET/CT is useful in the follow-up of castration resistant prostate cancer with skeletal metastases.

Mechanisms of Intrinsic Tumor Resistance to Immunotherapy

Directory of Open Access Journals (Sweden)

John Rieth

2018-05-01

Full Text Available An increased understanding of the interactions between the immune system and tumors has opened the door to immunotherapy for cancer patients. Despite some success with checkpoint inhibitors including ipilimumab, pembrolizumab, and nivolumab, most cancer patients remain unresponsive to such immunotherapy, likely due to intrinsic tumor resistance. The mechanisms most likely involve reducing the quantity and/or quality of antitumor lymphocytes, which ultimately are driven by any number of developments: tumor mutations and adaptations, reduced neoantigen generation or expression, indoleamine 2,3-dioxygenase (IDO overexpression, loss of phosphatase and tensin homologue (PTEN expression, and overexpression of the Wnt–β-catenin pathway. Current work in immunotherapy continues to identify various tumor resistance mechanisms; future work is needed to develop adjuvant treatments that target those mechanisms, in order to improve the efficacy of immunotherapy and to expand its scope.

Consumer attitudes towards castration of piglets and alternatives to surgical castration.

Science.gov (United States)

Fredriksen, Bente; Johnsen, Anne Mette Sibeko; Skuterud, Ellen

2011-04-01

From three in-depth focus group studies and an internet based study concerning consumers attitudes towards surgical castration of piglets and alternatives, it can be concluded that Norwegian consumers are content with the current practice of castration using local anaesthesia. They accept castration as a necessary means to prevent the risk of boar taint in meat and thereby secure meat quality. Even though castration using anaesthesia is not a perfect solution, it is considered sufficient, and the consumers do not ask for alternatives. Most consumers were sceptical of immunocastration. The scepticism was mainly based on the fear of residuals in meat and unknown long-term consequences for the consumers. On the other hand the confidence in Norwegian control authorities is considerable, and will probably contribute to the maintenance of purchase habits even if immunocastration is to be introduced in Norwegian pig production. Castration without anaesthesia was characterized as completely unacceptable. Copyright © 2010 Elsevier Ltd. All rights reserved.

Impact of cabazitaxel on 2-year survival and palliation of tumour-related pain in men with metastatic castration-resistant prostate cancer treated in the TROPIC trial

DEFF Research Database (Denmark)

Bahl, A; Oudard, S; Tombal, B

2013-01-01

Cabazitaxel significantly improves overall survival (OS) versus mitoxantrone in patients with metastatic castration-resistant prostate cancer after docetaxel failure. We examined patient survival at 2 years and tumour-related pain with cabazitaxel versus mitoxantrone....

Practical recommendations for radium-223 treatment of metastatic castration-resistant prostate cancer

International Nuclear Information System (INIS)

Du, Yong; Carrio, Ignasi; De Vincentis, Giuseppe; Fanti, Stefano; Ilhan, Harun; Mommsen, Caroline; Nitzsche, Egbert; Sundram, Francis; Vogel, Wouter; Oyen, Wim; Lewington, Val

2017-01-01

Radium Ra 223 dichloride (radium-223, Xofigo registered) is the first targeted alpha therapy for patients with castration-resistant prostate cancer and symptomatic bone metastases. Radium-223 provides a new treatment option for this setting, but also necessitates a new treatment management approach. We provide straightforward and practical recommendations for European nuclear medicine centres to optimize radium-223 service provision. An independent research consultancy agency observed radium-223 procedures and conducted interviews with all key staff members involved in radium-223 treatment delivery in 11 nuclear medicine centres across six countries (Germany, Italy, the Netherlands, Spain, Switzerland and the UK) experienced in administering radium-223. The findings were collated and discussed at a meeting of experts from these centres, during which key consensus recommendations were defined. The recommendations cover centre organization and preparation; patient referral; radium-223 ordering, preparation and disposal; radium-223 treatment delivery/administration; and patient experience. Guidance includes structured coordination and communication within centres and multidisciplinary teams, focusing on sharing best practice to provide high-quality, patient-centred care throughout the treatment pathway. These expert recommendations are intended to complement existing management guidelines. Sharing best practice and experience will help nuclear medicine centres to optimize radium-223 service provision and improve patient care. (orig.)

Practical recommendations for radium-223 treatment of metastatic castration-resistant prostate cancer

Energy Technology Data Exchange (ETDEWEB)

Du, Yong [The Royal Marsden NHS Foundation Trust, Department of Nuclear Medicine and PET/CT, London (United Kingdom); Carrio, Ignasi [Hospital Sant Pau, Barcelona (Spain); De Vincentis, Giuseppe [Policlinico Umberto I University Hospital Rome, Rome (Italy); Fanti, Stefano [University Hospital Bologna, Bologna (Italy); Ilhan, Harun [Ludwig-Maximilians-University Hospital, Munich (Germany); Mommsen, Caroline [Praxis fuer diagnostische und therapeutische Nuklearmedizin Berlin, Berlin (Germany); Nitzsche, Egbert [Canton Hospital Aarau, Aarau (Switzerland); Sundram, Francis [University Hospital Southampton NHS Foundation Trust, Southampton (United Kingdom); Vogel, Wouter [The Netherlands Cancer Institute, Amsterdam (Netherlands); Oyen, Wim [The Royal Marsden NHS Foundation Trust, Department of Nuclear Medicine and PET/CT, London (United Kingdom); The Institute of Cancer Research, London (United Kingdom); Lewington, Val [Guy' s and St Thomas' NHS Foundation Trust, London (United Kingdom)

2017-09-15

Radium Ra 223 dichloride (radium-223, Xofigo registered) is the first targeted alpha therapy for patients with castration-resistant prostate cancer and symptomatic bone metastases. Radium-223 provides a new treatment option for this setting, but also necessitates a new treatment management approach. We provide straightforward and practical recommendations for European nuclear medicine centres to optimize radium-223 service provision. An independent research consultancy agency observed radium-223 procedures and conducted interviews with all key staff members involved in radium-223 treatment delivery in 11 nuclear medicine centres across six countries (Germany, Italy, the Netherlands, Spain, Switzerland and the UK) experienced in administering radium-223. The findings were collated and discussed at a meeting of experts from these centres, during which key consensus recommendations were defined. The recommendations cover centre organization and preparation; patient referral; radium-223 ordering, preparation and disposal; radium-223 treatment delivery/administration; and patient experience. Guidance includes structured coordination and communication within centres and multidisciplinary teams, focusing on sharing best practice to provide high-quality, patient-centred care throughout the treatment pathway. These expert recommendations are intended to complement existing management guidelines. Sharing best practice and experience will help nuclear medicine centres to optimize radium-223 service provision and improve patient care. (orig.)

Effect of local anaesthesia and/or analgesia on pain responses induced by piglet castration

Directory of Open Access Journals (Sweden)

Nyman Görel

2011-05-01

Full Text Available Abstract Background Surgical castration in male piglets is painful and methods that reduce this pain are requested. This study evaluated the effect of local anaesthesia and analgesia on vocal, physiological and behavioural responses during and after castration. A second purpose was to evaluate if herdsmen can effectively administer anaesthesia. Methods Four male piglets in each of 141 litters in five herds were randomly assigned to one of four treatments: castration without local anaesthesia or analgesia (C, controls, analgesia (M, meloxicam, local anaesthesia (L, lidocaine, or both local anaesthesia and analgesia (LM. Lidocaine (L, LM was injected at least three minutes before castration and meloxicam (M, LM was injected after castration. During castration, vocalisation was measured and resistance movements judged. Behaviour observations were carried out on the castration day and the following day. The day after castration, castration wounds were ranked, ear and skin temperature was measured, and blood samples were collected for analysis of acute phase protein Serum Amyloid A concentration (SAA. Piglets were weighed on the castration day and at three weeks of age. Sickness treatments and mortality were recorded until three weeks of age. Results Piglets castrated with lidocaine produced calls with lower intensity (p p p = 0.06, n.s. and the following day (p = 0.02. Controls had less swollen wounds compared to piglets assigned to treatments M, L and LM (p p = 0.005; p = 0.05 for C + L compared to M + LM. Ear temperature was higher (p Conclusions The study concludes that lidocaine reduced pain during castration and that meloxicam reduced pain after castration. The study also concludes that the herdsmen were able to administer local anaesthesia effectively.

Src controls castration recurrence of CWR22 prostate cancer xenografts

International Nuclear Information System (INIS)

Su, Bing; Gillard, Bryan; Gao, Lingqiu; Eng, Kevin H; Gelman, Irwin H

2013-01-01

Recurrence of prostate cancer (CaP) after androgen-deprivation therapy continues to have the greatest impact on patient survival. Castration-recurrent (CR)-CaP is likely driven by the activation of androgen receptor (AR) through multiple mechanisms including induction of AR coregulators, AR mutants or splice variants, and AR posttranslational modification such as phosphorylation by Src-family and Ack1 tyrosine kinases. Here, we address whether Src is required for the CR growth of human CWR22 CaP xenografts. The shRNA-mediated Src knockdown or treatment with the Src inhibitors, dasatinib or KXO1, reduced CaP recurrence over controls and increased time-to-recurrence following castration. Moreover, CR-CaP [Src-shRNA] tumors that recurred had similar Src protein and activation levels as those of parental cells, strengthening the notion that Src activity is required for progression to CR-CaP. In contrast, the ability of dasatinib or KXO1 to inhibit Src kinase activity in vitro did not correlate with their ability to inhibit serum-driven in vitro proliferation of CR and androgen-dependent stable cell lines derived from CWR22 tumors (CWR22Rv1 and CWR22PC, respectively), suggesting that the in vitro proliferation of these CaP lines is Src independent. Taken together, these findings strongly suggest that Src is a potent and specific therapeutic target for CR-CaP progression

Development and Implementation of a High-Throughput High-Content Screening Assay to Identify Inhibitors of Androgen Receptor Nuclear Localization in Castration-Resistant Prostate Cancer Cells

Science.gov (United States)

Nguyen, Minh M.; Dar, Javid A.; Ai, Junkui; Wang, Yujuan; Masoodi, Khalid Z.; Shun, Tongying; Shinde, Sunita; Camarco, Daniel P.; Hua, Yun; Huryn, Donna M.; Wilson, Gabriela Mustata; Lazo, John S.; Nelson, Joel B.; Wipf, Peter

2016-01-01

Abstract Patients with castration-resistant prostate cancer (CRPC) can be treated with abiraterone, a potent inhibitor of androgen synthesis, or enzalutamide, a second-generation androgen receptor (AR) antagonist, both targeting AR signaling. However, most patients relapse after several months of therapy and a majority of patients with relapsed CRPC tumors express the AR target gene prostate-specific antigen (PSA), suggesting that AR signaling is reactivated and can be targeted again to inhibit the relapsed tumors. Novel small molecules capable of inhibiting AR function may lead to urgently needed therapies for patients resistant to abiraterone, enzalutamide, and/or other previously approved antiandrogen therapies. Here, we describe a high-throughput high-content screening (HCS) campaign to identify small-molecule inhibitors of AR nuclear localization in the C4-2 CRPC cell line stably transfected with GFP-AR-GFP (2GFP-AR). The implementation of this HCS assay to screen a National Institutes of Health library of 219,055 compounds led to the discovery of 3 small molecules capable of inhibiting AR nuclear localization and function in C4-2 cells, demonstrating the feasibility of using this cell-based phenotypic assay to identify small molecules targeting the subcellular localization of AR. Furthermore, the three hit compounds provide opportunities to develop novel AR drugs with potential for therapeutic intervention in CRPC patients who have relapsed after treatment with antiandrogens, such as abiraterone and/or enzalutamide. PMID:27187604

Genetic Determinants of Cisplatin Resistance in Patients With Advanced Germ Cell Tumors.

Science.gov (United States)

Bagrodia, Aditya; Lee, Byron H; Lee, William; Cha, Eugene K; Sfakianos, John P; Iyer, Gopa; Pietzak, Eugene J; Gao, Sizhi Paul; Zabor, Emily C; Ostrovnaya, Irina; Kaffenberger, Samuel D; Syed, Aijazuddin; Arcila, Maria E; Chaganti, Raju S; Kundra, Ritika; Eng, Jana; Hreiki, Joseph; Vacic, Vladimir; Arora, Kanika; Oschwald, Dayna M; Berger, Michael F; Bajorin, Dean F; Bains, Manjit S; Schultz, Nikolaus; Reuter, Victor E; Sheinfeld, Joel; Bosl, George J; Al-Ahmadie, Hikmat A; Solit, David B; Feldman, Darren R

2016-11-20

Purpose Owing to its exquisite chemotherapy sensitivity, most patients with metastatic germ cell tumors (GCTs) are cured with cisplatin-based chemotherapy. However, up to 30% of patients with advanced GCT exhibit cisplatin resistance, which requires intensive salvage treatment, and have a 50% risk of cancer-related death. To identify a genetic basis for cisplatin resistance, we performed whole-exome and targeted sequencing of cisplatin-sensitive and cisplatin-resistant GCTs. Methods Men with GCT who received a cisplatin-containing chemotherapy regimen and had available tumor tissue were eligible to participate in this study. Whole-exome sequencing or targeted exon-capture-based sequencing was performed on 180 tumors. Patients were categorized as cisplatin sensitive or cisplatin resistant by using a combination of postchemotherapy parameters, including serum tumor marker levels, radiology, and pathology at surgical resection of residual disease. Results TP53 alterations were present exclusively in cisplatin-resistant tumors and were particularly prevalent among primary mediastinal nonseminomas (72%). TP53 pathway alterations including MDM2 amplifications were more common among patients with adverse clinical features, categorized as poor risk according to the International Germ Cell Cancer Collaborative Group (IGCCCG) model. Despite this association, TP53 and MDM2 alterations predicted adverse prognosis independent of the IGCCCG model. Actionable alterations, including novel RAC1 mutations, were detected in 55% of cisplatin-resistant GCTs. Conclusion In GCT, TP53 and MDM2 alterations were associated with cisplatin resistance and inferior outcomes, independent of the IGCCCG model. The finding of frequent TP53 alterations among mediastinal primary nonseminomas may explain the more frequent chemoresistance observed with this tumor subtype. A substantial portion of cisplatin-resistant GCTs harbor actionable alterations, which might respond to targeted therapies. Genomic

Banding or Burdizzo castration and carprofen administration on peripheral leukocyte inflammatory cytokine transcripts.

Science.gov (United States)

Pang, W Y; Earley, B; Murray, M; Sweeney, T; Gath, V; Crowe, M A

2011-02-01

The objective was to investigate if Banding or Burdizzo castration of bulls would alter the gene expression profile of a range of peripheral leukocyte inflammatory cytokines (IL-1, IL-6, IL-8, IL-10, interferon-γ and tumor necrosis factor-α) and to determine if the administration of carprofen (C) before castration would affect the expression of these genes. Thirty Holstein-Friesian bulls (5.5 months; Mean 191±(SEM) 3.7 kg) were blocked by weight and randomly assigned to one of five treatments: (1) untreated control (CON); (2) Banding castration at 0 min (BAND); (3) BAND following an i.v. injection of 1.4 mg/kg BW of carprofen (C) at -20 min (BAND+C); (4) Burdizzo castration at 0 min (BURD); or (5) BURD following 1.4 mg/kg BW of carprofen at -20 min (BURD+C). Blood samples were collected at 1 h before castration and 6, 24 and 48 h post-castration for routine hematology and quantitative real-time PCR analysis of cytokine gene expression analysis. Generally, there were no differences (P>0.05) among treatment groups in hematological variables following castration. Cortisol concentrations were unchanged throughout the experimental period in CON bulls. BURD animals had greater cortisol concentrations than BAND and CON animals at 6 h post treatment. Transitory effects were observed only in the expression of IL-6 and TNF-α. The relative expression of IL-6 was greater in the BURD than in the BAND treatment (Pcarprofen administration can affect IL-6 gene expression levels in BURD castrated animals. Copyright © 2010 Elsevier Ltd. All rights reserved.

Preliminary experience on the use of the Adnatest® system for detection of circulating tumor cells in prostate cancer patients.

Science.gov (United States)

Todenhöfer, Tilman; Hennenlotter, Jörg; Feyerabend, Susan; Aufderklamm, Stefan; Mischinger, Johannes; Kühs, Ursula; Gerber, Valentina; Fetisch, Jasmin; Schilling, David; Hauch, Siegfried; Stenzl, Arnulf; Schwentner, Christian

2012-08-01

The Adnatest® system combines immunomagnetic enrichment of epithelial cells with polymerase chain reaction for prostate cancer (PC)-specific transcripts for the detection circulating tumor cells (CTCs). We evaluated the Adnatest® in patients with castration-resistant PC receiving docetaxel chemotherapy. CTCs were assessed in 16 patients with castration-resistant PC before cycles one and three of chemotherapy. Furthermore, markers of stem cells and epithelial-mesenchymal transition were assessed. Treatment response was assessed by imaging and prostate-specific antigen measurements. Before chemotherapy, 11 patients were Adnatest®-positive whereas five patients were Adnatest®-positive before cycle three. A positive Adnatest® correlated with radiological progression (p=0.02). Rates of disease progression in epidermal growth factor receptor (EGFR)-positive and -negative patients were 100% and 7.7% (p=0.03). In this preliminary study, the Adnatest® detected CTCs in a considerable proportion of patients with castration-resistant PC. First data on certain markers (EGFR and aldehyd dehydrogenase 1) encourage future studies investigating transcripts predicting treatment response.

WE-H-BRA-03: Development of a Model to Include the Evolution of Resistant Tumor Subpopulations Into the Treatment Optimization Process for Schedules Involving Targeted Agents in Chemoradiation Therapy

International Nuclear Information System (INIS)

Grassberger, C; Paganetti, H

2016-01-01

Purpose: To develop a model that includes the process of resistance development into the treatment optimization process for schedules that include targeted therapies. Further, to validate the approach using clinical data and to apply the model to assess the optimal induction period with targeted agents before curative treatment with chemo-radiation in stage III lung cancer. Methods: Growth of the tumor and its subpopulations is modeled by Gompertzian growth dynamics, resistance induction as a stochastic process. Chemotherapy induced cell kill is modeled by log-cell kill dynamics, targeted agents similarly but restricted to the sensitive population. Radiation induced cell kill is assumed to follow the linear-quadratic model. The validation patient data consist of a cohort of lung cancer patients treated with tyrosine kinase inhibitors that had longitudinal imaging data available. Results: The resistance induction model was successfully validated using clinical trial data from 49 patients treated with targeted agents. The observed recurrence kinetics, with tumors progressing from 1.4–63 months, result in tumor growth equaling a median volume doubling time of 92 days [34–248] and a median fraction of pre-existing resistance of 0.035 [0–0.22], in agreement with previous clinical studies. The model revealed widely varying optimal time points for the use of curative therapy, reaching from ∼1m to >6m depending on the patient’s growth rate and amount of pre-existing resistance. This demonstrates the importance of patient-specific treatment schedules when targeted agents are incorporated into the treatment. Conclusion: We developed a model including evolutionary dynamics of resistant sub-populations with traditional chemotherapy and radiation cell kill models. Fitting to clinical data yielded patient specific growth rates and resistant fraction in agreement with previous studies. Further application of the model demonstrated how proper timing of chemo

WE-H-BRA-03: Development of a Model to Include the Evolution of Resistant Tumor Subpopulations Into the Treatment Optimization Process for Schedules Involving Targeted Agents in Chemoradiation Therapy

Energy Technology Data Exchange (ETDEWEB)

Grassberger, C; Paganetti, H [Massachusetts General Hospital, Boston, MA (United States)

2016-06-15

Purpose: To develop a model that includes the process of resistance development into the treatment optimization process for schedules that include targeted therapies. Further, to validate the approach using clinical data and to apply the model to assess the optimal induction period with targeted agents before curative treatment with chemo-radiation in stage III lung cancer. Methods: Growth of the tumor and its subpopulations is modeled by Gompertzian growth dynamics, resistance induction as a stochastic process. Chemotherapy induced cell kill is modeled by log-cell kill dynamics, targeted agents similarly but restricted to the sensitive population. Radiation induced cell kill is assumed to follow the linear-quadratic model. The validation patient data consist of a cohort of lung cancer patients treated with tyrosine kinase inhibitors that had longitudinal imaging data available. Results: The resistance induction model was successfully validated using clinical trial data from 49 patients treated with targeted agents. The observed recurrence kinetics, with tumors progressing from 1.4–63 months, result in tumor growth equaling a median volume doubling time of 92 days [34–248] and a median fraction of pre-existing resistance of 0.035 [0–0.22], in agreement with previous clinical studies. The model revealed widely varying optimal time points for the use of curative therapy, reaching from ∼1m to >6m depending on the patient’s growth rate and amount of pre-existing resistance. This demonstrates the importance of patient-specific treatment schedules when targeted agents are incorporated into the treatment. Conclusion: We developed a model including evolutionary dynamics of resistant sub-populations with traditional chemotherapy and radiation cell kill models. Fitting to clinical data yielded patient specific growth rates and resistant fraction in agreement with previous studies. Further application of the model demonstrated how proper timing of chemo

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......-negative group, respectively. Compared to a model omitting ERG-status, the ERG-stratified model showed comparable AUC values 1 year (77.6% vs. 78.0%, P = 0.82), 2 years (71.7% vs. 71.8%, P = 0.85), 5 years (68.5% vs. 69.9%, P = 0.32), and 8 years (67.9% vs. 71.4%, P = 0.21) from ADT initiation. No differences...

Phase III Study of Cabozantinib in Previously Treated Metastatic Castration-Resistant Prostate Cancer: COMET-1.

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Smith, Matthew; De Bono, Johann; Sternberg, Cora; Le Moulec, Sylvestre; Oudard, Stéphane; De Giorgi, Ugo; Krainer, Michael; Bergman, Andries; Hoelzer, Wolfgang; De Wit, Ronald; Bögemann, Martin; Saad, Fred; Cruciani, Giorgio; Thiery-Vuillemin, Antoine; Feyerabend, Susan; Miller, Kurt; Houédé, Nadine; Hussain, Syed; Lam, Elaine; Polikoff, Jonathan; Stenzl, Arnulf; Mainwaring, Paul; Ramies, David; Hessel, Colin; Weitzman, Aaron; Fizazi, Karim

2016-09-01

Cabozantinib is an inhibitor of kinases, including MET and vascular endothelial growth factor receptors, and has shown activity in men with previously treated metastatic castration-resistant prostate cancer (mCRPC). This blinded phase III trial compared cabozantinib with prednisone in patients with mCRPC. Men with progressive mCRPC after docetaxel and abiraterone and/or enzalutamide were randomly assigned at a two-to-one ratio to cabozantinib 60 mg once per day or prednisone 5 mg twice per day. The primary end point was overall survival (OS). Bone scan response (BSR) at week 12 as assessed by independent review committee was the secondary end point; radiographic progression-free survival (rPFS) and effects on circulating tumor cells (CTCs), bone biomarkers, serum prostate-specific antigen (PSA), and symptomatic skeletal events (SSEs) were exploratory assessments. A total of 1,028 patients were randomly assigned to cabozantinib (n = 682) or prednisone (n = 346). Median OS was 11.0 months with cabozantinib and 9.8 months with prednisone (hazard ratio, 0.90; 95% CI, 0.76 to 1.06; stratified log-rank P = .213). BSR at week 12 favored cabozantinib (42% v 3%; stratified Cochran-Mantel-Haenszel P < .001). rPFS was improved in the cabozantinib group (median, 5.6 v 2.8 months; hazard ratio, 0.48; 95% CI, 0.40 to 0.57; stratified log-rank P < .001). Cabozantinib was associated with improvements in CTC conversion, bone biomarkers, and post-random assignment incidence of SSEs but not PSA outcomes. Grade 3 to 4 adverse events and discontinuations because of adverse events were higher with cabozantinib than with prednisone (71% v 56% and 33% v 12%, respectively). Cabozantinib did not significantly improve OS compared with prednisone in heavily treated patients with mCRPC and progressive disease after docetaxel and abiraterone and/or enzalutamide. Cabozantinib had some activity in improving BSR, rPFS, SSEs, CTC conversions, and bone biomarkers but not PSA outcomes. © 2016 by

Safety of Abiraterone Acetate in Castration-resistant Prostate Cancer Patients With Concomitant Cardiovascular Risk Factors.

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Procopio, Giuseppe; Grassi, Paolo; Testa, Isabella; Verzoni, Elena; Torri, Valter; Salvioni, Roberto; Valdagni, Riccardo; de Braud, Filippo

2015-10-01

The aim of this study was to evaluate the safety profile of abiraterone acetate (AA) in metastatic castration-resistant prostate cancer (mCRPC) men with cardiovascular comorbidity, as little conclusive safety data are available in this patient subset. A retrospective analysis of mCRPC patients with controlled cardiovascular comorbidities, receiving AA 1000 mg administered orally once daily and prednisone 5 mg twice daily, between April 2011 and July 2012, was performed. All clinical and instrumental variables and toxicity data were analyzed by descriptive statistics: mean, standard deviation, minimum and maximum values for continuous variables, and absolute and relative frequencies for categorical variables. A total of 51 mCRPC patients were evaluated. Metastatic sites included the bone (74%), lungs, and liver (26%). All patients were previously treated with at least 2 lines of hormone and 1 docetaxel-based chemotherapy. Preexisting cardiac risk factors included hypertension (41%), cardiac ischemia (12%), arrhythmias (6%), dislipidemia (18%), and hyperglycemia (30%). No grade 3-4 adverse events were observed. Grade 1-2 adverse events included fluid retention (18%), asthenia (15%), and hypertension (16%). Median progression-free survival was 5.1 months (95% confidence interval, 0.5-12). Prostate specific antigen assessment revealed a good overall disease control rate (64%). AA appears to be safe and well tolerated even in patients with cardiovascular comorbidities or with increased risk factors for cardiovascular diseases.

Progress toward overcoming hypoxia-induced resistance to solid tumor therapy

International Nuclear Information System (INIS)

Karakashev, Sergey V; Reginato, Mauricio J

2015-01-01

Hypoxic tumors are associated with poor clinical outcome for multiple types of human cancer. This may be due, in part, to hypoxic cancer cells being resistant to anticancer therapy, including radiation therapy, chemotherapy, and targeted therapy. Hypoxia inducible factor 1, a major regulator of cellular response to hypoxia, regulates the expression of genes that are involved in multiple aspects of cancer biology, including cell survival, proliferation, metabolism, invasion, and angiogenesis. Here, we review multiple pathways regulated by hypoxia/hypoxia inducible factor 1 in cancer cells and discuss the latest advancements in overcoming hypoxia-mediated tumor resistance

PET/CT With 68Ga-DOTA-TATE for Diagnosis of Neuroendocrine: Differentiation in Patients With Castrate-Resistant Prostate Cancer.

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Gofrit, Ofer Nathan; Frank, Stephen; Meirovitz, Amichay; Nechushtan, Hovav; Orevi, Marina

2017-01-01

Castrate-resistant prostate cancer (CRPC) often shows histological evidence of neuroendocrine differentiation (NED). To evaluate the extent of NED in patients with CRPC, we used PET/CT with Ga-[DOTA-Tyr]-octreotate (Ga-DOTA-TATE), a somatostatin analog that binds somatostatin receptor 2 with high affinity. This radiotracer is used in imaging of neuroendocrine tumors. Twelve patients (mean age, 65 [SD, 12] years) with CRPC were studied. Their mean prostate-specific antigen level at scanning was 85.6 (SD, 144.6) ng/mL. PET/CT images were obtained after the injection of 120 to 200 MBq of Ga-DOTA-TATE. All participants had at least 1 blastic metastasis demonstrating uptake of Ga-DOTA-TATE (mean SUVmax of 5.3 [SD, 2.3]). In 6 patients, moderately high to high uptakes (SUVmax, >5) were seen. Patients with multiple bone metastases had a significantly higher SUVmax compared with patients with few metastases (mean of 5.8 vs 3.8, P = 0.05). In 4 patients, lytic bone lesions or lymph node metastases also showed uptake of the tracer (mean SUVmax of 7.2 [SD, 3.2]). Uptake of the radiotracer was also observed in bones showing normal architecture in CT, suggesting that NED cells appear early during metastases development. Uptake of Ga-DOTA-TATE is a common finding in metastases of CRPC patients, suggesting that NED is frequent in these patients. In half of the patients, widespread uptake of Ga-DOTA-TATE was observed. This suggests that the possibility of treating selected CRCP patients with anti-neuroendocrine tumor therapies should be explored and that Ga-DOTA-TATE scanning could have a role in predicting the efficacy of these treatments.

Two cases of paraprostatic cysts in castrated male dogs.

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Goodrich, Zachary J; Wilke, Vicki L; Root Kustritz, Margaret V

2011-01-01

Two castrated male dogs presented for evaluation of tenesmus. Presurgical evaluations included complete physical examinations, serum biochemistry, abdominal ultrasonography, and MRI (case 2 only). Paraprostatic cysts were diagnosed in both cases based on the results of abdominal ultrasonography, MRI, and histopathology of tissue samples obtained during exploratory laparotomy. To the authors' knowledge, the two cases presented herein are the first documented cases of paraprostatic cysts that developed after castration in male dogs. Paraprostatic cysts should be considered in the differential diagnoses for castrated male dogs with prostatic disease.

Using a Novel Transgenic Mouse Model to Study c-Myc Oncogenic Pathway in Castration Resistance and Chemoresistance of Prostate Cancer

Science.gov (United States)

2017-12-01

AWARD NUMBER: W81XWH-13-1-0162 TITLE: Using a Novel Transgenic Mouse Model to Study c -Myc Oncogenic Pathway in Castration Resistance and...DATES COVERED 15Sept2013 - 14Sept2017 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Using a Novel Transgenic Mouse Model to Study c -Myc Oncogenic...ABSTRACT We previously made a PB-Cre4/Ai-Myc model for Cre-induced and androgen-independent expression of c -Myc and Luc2 in prostate. This is designed

Effect of surgical and immunological castration on haematological ...

African Journals Online (AJOL)

The PCV and HB of dogs surgically castrated increased progressively up to16th week after castration but only up to10 weeks in dogs immunologically castrated. Both PCV and HB decreased progressively after 10 weeks in dogs immunologically castrated. Similarly, the WBC of dogs surgically castrated steadily increased ...

Curcumin induces apoptosis and protective autophagy in castration-resistant prostate cancer cells through iron chelation

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Yang C

2017-02-01

Full Text Available Chunguang Yang,1,* Xueyou Ma,1,* Zhihua Wang,1 Xing Zeng,1 Zhiquan Hu,1 Zhangqun Ye,1 Guanxin Shen2 1Department of Urology, Tongji Hospital, 2Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China *These authors contributed equally to this work Background: Curcumin induces apoptosis and autophagy in different cancer cells. Moreover, chemical and biological experiments have evidenced that curcumin is a biologically active iron chelator and induces cytotoxicity through iron chelation. We thus hypothesized that curcumin may induce apoptosis and autophagy in castration-resistant prostate cancer (CRPC cells through its iron-chelating properties.Materials and methods: CRPC cells were loaded with curcumin alone or in combination with ferric ammonium citrate (FAC. Cytotoxicity was measured by 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT assay. Apoptosis was assessed by flow cytometry, terminal deoxynucleotidyl transferase nick end labeling (TUNEL assay and caspase activity. Autophagy status was analyzed by the detection of autophagosomes and light chain 3-II (LC3-II using transmission electron microscopy and Western blot. Iron-binding activity of curcumin was assessed by spectrophotometry and MTT assay. The expression levels of transferrin receptor 1 (TfR1 and iron regulatory protein 1 (IRP1 were examined by Western blot.Results: Curcumin induced apoptosis and autophagy in CRPC cells. Combining curcumin with autophagy inhibitors (3-methyladenine [3-MA] synergized the apoptotic effect of curcumin. Moreover, curcumin bound to FAC at a ratio of ~1:1, as assessed by spectrophotometry and MTT assay. Apoptosis and autophagy induced by curcumin were counteracted by equal amounts of FAC. At apoptosis- and autophagy-inducing concentrations, curcumin enhanced the expression levels of TfR1 and IRP1, indicative of iron deprivation induced by curcumin

Radium-223 in treatment of castration-resistant prostate cancer with skeletal metastases

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V. B. Matveev

2017-01-01

Full Text Available More than 90 % of patients with metastatic castration-resistant prostate cancer (CRPC have radiologically confirmed skeletal metastases. Traditional treatment methods such as administration of painkillers, external beam therapy, bisphosphonates or denosumab, as well as injections of strontium-89 or samarium-153 radionuclides, have only palliative effect and in some cases can postpone development of skeletal complications. Alpha-emitter radium-223 dichloride (Ra-223; alpharadin previously is currently one of the known drugs with proven effectiveness in relation to increasing overall survival of patients with CRPC. Ra-223 was developed specifically for patients with CRPC and symptomatic skeletal metastases. The drug targets the areas of skeletal tissue remodeling. Ra-223 is the therapy of choice in patients with CRPC and skeletal metastases and without confirmed visceral metastases before and after docetaxel chemotherapy. Chemotherapy after treatment with Ra-223 is a possible and satisfactory tolerable treatment option. Combination of Ra-223 with abiraterone, enzalutamide, or denosumab is, apparently, effective and safe, but further studies are necessary.

Dendritic cell vaccination in combination with docetaxel for patients with metastatic castration-resistant prostate cancer

DEFF Research Database (Denmark)

Kongsted, Per; Borch, Troels Holz; Ellebaek, Eva

2017-01-01

Background aims  We investigated whether the addition of an autologous dendritic cell–based cancer vaccine (DCvac) induces an immune response in patients with metastatic castration-resistant prostate cancer treated with docetaxel.  Methods  Forty-three patients were randomized 1:1 to receive up...... twice through treatment cycles 1–4 and once through treatment cycles 5–10. Immune cell composition and antigen-specific responses were analyzed using flow cytometry, ELISpot and delayed type hypersensitivity (DTH) tests. Toxicity was graded according to Common Terminology Criteria for Adverse Events...... to local reactions. Decline in myeloid-derived suppressor cells at the third treatment cycle was found to be an independent predictor of DSS.  Conclusions  The addition of DCvac was safe. Immune responses were detected in approximately half of the patients investigated....

Body measurements and carcass traits of castrated and non-castrated Mediterranean buffalos

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Renata de Oliveira Santos Ramalho

2013-01-01

Full Text Available In this study was evaluated the effect of sex condition on body measurements and carcass traits as well as the correlations between them, using data of 20 Mediterranean, from Fazenda Três Rios, at Casimiro de Abreu, Rio de Janeiro, managed in tangola grass pasture, receiving mineral salt ad libitum, slaughtered at approximately 462,05 kg (±28.34. The body measurements were: thoracic depth (TD, croup length (CL, withers height (WH, rump width (RW, rump height (RH, ischium distance (ID, cushion thickness (CT, thoracic perimeter (TP, and dorsal line length (DLL. Data were submited to variance analysis and Pearson correlation. The castrated animals presented higher height of croup. Non-castrated animals had bigger yield from leather than the castrated animals, which influenced the lowest yield of carcass regarding the castrated ones. There was no difference for yield of paws, innards and head in function of the sexual condition. There was significant correlation between the slaughter weight (SW and the following corporal measures: TP, TD, RW, ID and WH.

Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial

DEFF Research Database (Denmark)

Kwon, Eugene D; Drake, Charles G; Scher, Howard I

2014-01-01

BACKGROUND: Ipilimumab is a fully human monoclonal antibody that binds cytotoxic T-lymphocyte antigen 4 to enhance antitumour immunity. Our aim was to assess the use of ipilimumab after radiotherapy in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel...... chemotherapy. METHODS: We did a multicentre, randomised, double-blind, phase 3 trial in which men with at least one bone metastasis from castration-resistant prostate cancer that had progressed after docetaxel treatment were randomly assigned in a 1:1 ratio to receive bone-directed radiotherapy (8 Gy in one...... fraction) followed by either ipilimumab 10 mg/kg or placebo every 3 weeks for up to four doses. Non-progressing patients could continue to receive ipilimumab at 10 mg/kg or placebo as maintenance therapy every 3 months until disease progression, unacceptable toxic effect, or death. Patients were randomly...

Radiation induction of drug resistance in RIF-1: Correlation of tumor and cell culture results

International Nuclear Information System (INIS)

Moulder, J.E.; Hopwood, L.E.; Volk, D.M.; Davies, B.M.

1991-01-01

The RIF-1 tumor line contains cells that are resistant to various anti-neoplastic drugs, including 5-fluorouracil (5FU), methotrexate (MTX), adriamycin (ADR), and etoposide (VP16). The frequency of these drug-resistant cells is increased after irradiation. The frequency of drug-resistant cells and the magnitude of radiation-induced drug resistance are different in cell culture than in tumors. The dose-response and expression time relationships for radiation induction of drug resistance observed in RIF-1 tumors are unusual.We hypothesize that at high radiation doses in vivo, we are selecting for cells that are both drug resistant and radiation resistant due to microenvironmental factors, whereas at low radiation doses in vivo and all radiation doses in vitro, we are observing true mutants. These studies indicate that there can be significant differences in drug-resistance frequencies between tumors and their cell lines of origin, and that radiation induction of drug resistance depends significantly on whether the induction is done in tumors or in cell culture. These results imply that theories about the induction of drug resistance that are based on cell culture studies may be inapplicable to the induction of drug resistance in tumors

Gender Preference in the Sexual Attractions, Fantasies, and Relationships of Voluntarily Castrated Men.

Science.gov (United States)

Handy, Ariel B; Jackowich, Robyn A; Wibowo, Erik; Johnson, Thomas Wayne; Wassersug, Richard J

2016-03-01

Some men seek castration outside a clear medical need. This study explored how their sexuality changed after castration. To explore changes in preferred gender(s) of sexual attraction, fantasy, and relationships in voluntarily castrated men with or without gonadal hormone therapy. A questionnaire was posted at http://www.eunuch.org that yielded data on men who had been voluntarily castrated physically (n = 198) or chemically (n = 96). Respondents were asked to report retrospectively on their sexuality, including their sexual activity and which gender(s) they were sexually attracted to, fantasized about, or had sexual relations with 6 months to 1 year before and after castration. A substantial proportion of men remained sexually active after castration; 37% had sex at least several times per week. Most respondents did not report a change in preferred gender(s) of attraction (65%, n = 181), fantasies (62%, n = 169), or sexual relationships (66%, n = 163), although approximately 20% to 30% of respondents did report such changes and 8% to 11% became non-sexual after castration. Respondents who were attracted to and fantasized about "only men" or who had sexual relationship with "only women" before castration were the least likely to report a change subsequent to castration. Respondents who were taking neither supplemental testosterone nor estrogen were more likely to report (i) becoming attracted to no one, (ii) fantasizing about no one, and (iii) becoming sexually inactive. Sexual changes in voluntarily castrated men vary and can be influenced by various factors including the use of supplemental testosterone or estrogen therapy. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Suppression of LIM and SH3 Domain Protein 1 (LASP1) Negatively Regulated by Androgen Receptor Delays Castration Resistant Prostate Cancer Progression.

Science.gov (United States)

Dejima, Takashi; Imada, Kenjiro; Takeuchi, Ario; Shiota, Masaki; Leong, Jeffrey; Tombe, Tabitha; Tam, Kevin; Fazli, Ladan; Naito, Seiji; Gleave, Martin E; Ong, Christopher J

2017-02-01

LIM and SH3 domain protein 1 (LASP1) has been implicated in several human malignancies and has been shown to predict PSA recurrence in prostate cancer. However, the anti-tumor effect of LASP1 knockdown and the association between LASP1 and the androgen receptor (AR) remains unclear. The aim of this study is to clarify the significance of LASP1 as a target for prostate cancer, and to test the effect of silencing LASP1 in vivo using antisense oligonucleotides (ASO). A tissue microarray (TMA) was performed to characterize the differences in LASP1 expression in prostate cancer treated after hormone deprivation therapy. Flow cytometry was used to analyze cell cycle. We designed LASP1 ASO for knockdown of LASP1 in vivo studies. The expression of LASP1 in TMA was increased after androgen ablation and persisted in castration resistant prostate cancer (CRPC). Also in TMA, compared with LNCaP cell, LASP1 expression is elevated in CRPC cell lines (C4-2 and VehA cells). Interestingly, suppression of AR elevated LASP1 expression conversely, AR activation decreased LASP1 expression. Silencing of LASP1 reduced cell growth through G1 arrest which was accompanied by a decrease of cyclin D1. Forced overexpression of LASP1 promoted cell cycle and induced cell growth which was accompanied by an increase of cyclin D1. Systemic administration of LASP1 ASO with athymic mice significantly inhibited tumor growth in CRPC xenografts. These results indicate that LASP1 is negatively regulated by AR at the transcriptional level and promotes tumor growth through induction of cell cycle, ultimately suggesting that LASP1 may be a potential target in prostate cancer treatment. Prostate 77:309-320, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Circulating tumor cell counts are prognostic of overall survival in SWOG S0421: a phase III trial of docetaxel with or without atrasentan for metastatic castration-resistant prostate cancer.

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Goldkorn, Amir; Ely, Benjamin; Quinn, David I; Tangen, Catherine M; Fink, Louis M; Xu, Tong; Twardowski, Przemyslaw; Van Veldhuizen, Peter J; Agarwal, Neeraj; Carducci, Michael A; Monk, J Paul; Datar, Ram H; Garzotto, Mark; Mack, Philip C; Lara, Primo; Higano, Celestia S; Hussain, Maha; Thompson, Ian Murchie; Cote, Richard J; Vogelzang, Nicholas J

2014-04-10

Circulating tumor cell (CTC) enumeration has not been prospectively validated in standard first-line docetaxel treatment for metastatic castration-resistant prostate cancer. We assessed the prognostic value of CTCs for overall survival (OS) and disease response in S0421, a phase III trial of docetaxel plus prednisone with or without atrasentan. CTCs were enumerated at baseline (day 0) and before cycle two (day 21) using CellSearch. Baseline counts and changes in counts from day 0 to 21 were evaluated for association with OS, prostate-specific antigen (PSA), and RECIST response using Cox regression as well as receiver operator characteristic (ROC) curves, integrated discrimination improvement (IDI) analysis, and regression trees. Median day-0 CTC count was five cells per 7.5 mL, and CTCs < versus ≥ five per 7.5 mL were significantly associated with baseline PSA, bone pain, liver disease, hemoglobin, alkaline phosphatase, and subsequent PSA and RECIST response. Median OS was 26 months for < five versus 13 months for ≥ five CTCs per 7.5 mL at day 0 (hazard ratio [HR], 2.74 [adjusting for covariates]). ROC curves had higher areas under the curve for day-0 CTCs than for PSA, and IDI analysis showed that adding day-0 CTCs to baseline PSA and other covariates increased predictive accuracy for survival by 8% to 10%. Regression trees yielded new prognostic subgroups, and rising CTC count from day 0 to 21 was associated with shorter OS (HR, 2.55). These data validate the prognostic utility of CTC enumeration in a large docetaxel-based prospective cohort. Baseline CTC counts were prognostic, and rising CTCs at 3 weeks heralded significantly worse OS, potentially serving as an early metric to help redirect and optimize therapy in this clinical setting.

Eunuchs in contemporary society: characterizing men who are voluntarily castrated (part I).

Science.gov (United States)

Johnson, Thomas W; Brett, Michelle A; Roberts, Lesley F; Wassersug, Richard J

2007-07-01

Some males desire to be emasculated for no medical reason. These individuals are often secretive about their desires and little is known about their background and motivation. We sought to characterize these modern eunuchs and to identify risk factors for genital self-mutilation or self-administered chemical castration. We posted a questionnaire on the Eunuch Archive ( http://www.eunuch.org) that was responded to by 135 voluntarily castrated males. Questionnaire data were supplemented by accompanying narrative responses and several personal interviews. Participants answered questionnaire items pertaining to their knowledge about androgen deprivation, the nature of their castration, and the length of time between initial presentation of castration paraphilia and castration. These questionnaire data allowed us to compare and contrast voluntary chemical and physical eunuchs. The physical castrations were largely premeditated, with an average of 18 years from the time that an individual developed interest in being a eunuch to the time of their actual castration. We identified four factors that may promote castration ideations: (i) abuse sustained during childhood, including parental threats of castration; (ii) homosexuality; (iii) exposure to animal castration during youth; and (iv) religious condemnation of sexuality. Chemical eunuchs were more likely to have sought castration for libido control or to advance transition from male to female (P Body Integrity Identity Disorder and Gender Identity Disorders occur among those who self-identify as eunuch. We present evidence that the majority of self-identified voluntary eunuchs are not male-to-female transsexuals. Whereas the majority identify as male, many view themselves as in an alternate nonmale, nonfemale, gender space. We therefore suggest that male-to-eunuch is a valid transgender identity.

Differential requirements of androgen receptor in luminal progenitors during prostate regeneration and tumor initiation

Science.gov (United States)

Chua, Chee Wai; Epsi, Nusrat J; Leung, Eva Y; Xuan, Shouhong; Lei, Ming; Li, Bo I; Bergren, Sarah K; Hibshoosh, Hanina; Mitrofanova, Antonina

2018-01-01

Master regulatory genes of tissue specification play key roles in stem/progenitor cells and are often important in cancer. In the prostate, androgen receptor (AR) is a master regulator essential for development and tumorigenesis, but its specific functions in prostate stem/progenitor cells have not been elucidated. We have investigated AR function in CARNs (CAstration-Resistant Nkx3.1-expressing cells), a luminal stem/progenitor cell that functions in prostate regeneration. Using genetically--engineered mouse models and novel prostate epithelial cell lines, we find that progenitor properties of CARNs are largely unaffected by AR deletion, apart from decreased proliferation in vivo. Furthermore, AR loss suppresses tumor formation after deletion of the Pten tumor suppressor in CARNs; however, combined Pten deletion and activation of oncogenic Kras in AR-deleted CARNs result in tumors with focal neuroendocrine differentiation. Our findings show that AR modulates specific progenitor properties of CARNs, including their ability to serve as a cell of origin for prostate cancer. PMID:29334357

Lymphocyte function following radium-223 therapy in patients with metastasized, castration-resistant prostate cancer

Energy Technology Data Exchange (ETDEWEB)

Barsegian, Vahe; Moeckel, Daniel [Helios Kliniken, Institute of Nuclear Medicine, Schwerin (Germany); Mueller, Stefan P.; Bockisch, Andreas [University Hospital Essen, Department of Nuclear Medicine, Essen (Germany); Horn, Peter A.; Lindemann, Monika [University Hospital Essen, Institute for Transfusion Medicine, Essen (Germany)

2017-02-15

Therapy with the alpha-emitter radium-223 chloride ({sup 223}Ra) is an innovative therapeutic option in patients with metastasized, castration-resistant prostate cancer. However, radiotherapy can lead to hematopoietic toxicity. The aim of this study was to determine if {sup 223}Ra therapy induces an impairment of cellular antimicrobial immune responses. In 11 patients receiving {sup 223}Ra treatment, lymphocyte proliferation and the production of pro- and anti-inflammatory cytokines (interferon-γ and interleukin-10) were determined, using lymphocyte transformation testing and ELISpot, respectively. Lymphocyte function after stimulation with mitogens and microbial antigens was assessed prior to therapy and at day 1, 7 and 28 after therapy. Lymphocyte proliferation and the production of interferon-γ and interleukin-10 towards mitogens and antigens remained unchanged after therapy. Consistent with these in vitro data, we did not observe infectious complications after treatment. The results argue against an impairment of lymphocyte function after {sup 223}Ra therapy. Thus, immune responses against pathogens should remain unaffected. (orig.)

Minnelide Inhibits Androgen Dependent, Castration Resistant Prostate Cancer Growth by Decreasing Expression of Androgen Receptor Full Length and Splice Variants.

Science.gov (United States)

Isharwal, Sumit; Modi, Shrey; Arora, Nivedita; Uhlrich, Charles; Giri, Bhuwan; Barlass, Usman; Soubra, Ayman; Chugh, Rohit; Dehm, Scott M; Dudeja, Vikas; Saluja, Ashok; Banerjee, Sulagna; Konety, Badrinath

2017-05-01

With almost 30,000 deaths per year, prostate cancer is the second-leading cause of cancer-related death in men. Androgen Deprivation Therapy (ADT) has been the corner stone of prostate cancer treatment for decades. However, despite an initial response of prostate cancer to ADT, this eventually fails and the tumors recur, resulting in Castration Resistant Prostate Cancer (CRPC). Triptolide, a diterpene triepoxide, has been tested for its anti-tumor properties in a number of cancers for over a decade. Owing to its poor solubility in aqueous medium, its clinical application had been limited. To circumvent this problem, we have synthesized a water-soluble pro-drug of triptolide, Minnelide, that is currently being evaluated in a Phase 1 clinical trial against gastrointestinal tumors. In the current study, we assessed the therapeutic potential of Minnelide and its active compound triptolide against androgen dependent prostate cancer both in vitro as well as in vivo. Cell viability was measured by a MTT based assay after treating prostate cancer cells with multiple doses of triptolide. Apoptotic cell death was measured using a caspase 3/7 activity. Androgen Receptor (AR) promoter-binding activity was evaluated by using luciferase reporter assay. For evaluating the effect in vivo, 22Rv1 cells were implanted subcutaneously in animals, following which, treatment was started with 0.21 mg/kg Minnelide. Our study showed that treatment with triptolide induced apoptotic cell death in CRPC cells. Triptolide treatment inhibited AR transcriptional activity and decreased the expression of AR and its splice variants both at the mRNA and the protein level. Our studies show that triptolide inhibits nuclear translocation of Sp1, resulting in its decreased transcriptional activity leading to downregulation of AR and its splice variants in prostate cancer cells. In vivo, Minnelide (0.21 mg/kg) regressed subcutaneous tumors derived from CRPC 22RV1 at our study endpoint. Our animal

Trading in your spindles for blebs: the amoeboid tumor cell phenotype in prostate cancer

Directory of Open Access Journals (Sweden)

Samantha Morley

2014-08-01

Full Text Available Prostate cancer (PCa remains a principal cause of mortality in developed countries. Because no clinical interventions overcome resistance to androgen ablation therapy, management of castration resistance and metastatic disease remains largely untreatable. Metastasis is a multistep process in which tumor cells lose cell-cell contacts, egress from the primary tumor, intravasate, survive shear stress within the vasculature and extravasate into tissues to colonize ectopic sites. Tumor cells reestablish migratory behaviors employed during nonneoplastic processes such as embryonic development, leukocyte trafficking and wound healing. While mesenchymal motility is an established paradigm of dissemination, an alternate, 'amoeboid' phenotype is increasingly appreciated as relevant to human cancer. Here we discuss characteristics and pathways underlying the phenotype, and highlight our findings that the cytoskeletal regulator DIAPH3 governs the mesenchymal-amoeboid transition. We also describe our identification of a new class of tumor-derived microvesicles, large oncosomes, produced by amoeboid cells and with potential clinical utility in prostate and other cancers.

Inhibition of glycogen synthase kinase-3β counteracts ligand-independent activity of the androgen receptor in castration resistant prostate cancer.

Directory of Open Access Journals (Sweden)

Stefanie V Schütz

Full Text Available In order to generate genomic signals, the androgen receptor (AR has to be transported into the nucleus upon androgenic stimuli. However, there is evidence from in vitro experiments that in castration-resistant prostate cancer (CRPC cells the AR is able to translocate into the nucleus in a ligand-independent manner. The recent finding that inhibition of the glycogen-synthase-kinase 3β (GSK-3β induces a rapid nuclear export of the AR in androgen-stimulated prostate cancer cells prompted us to analyze the effects of a GSK-3β inhibition in the castration-resistant LNCaP sublines C4-2 and LNCaP-SSR. Both cell lines exhibit high levels of nuclear AR in the absence of androgenic stimuli. Exposure of these cells to the maleimide SB216763, a potent GSK-3β inhibitor, resulted in a rapid nuclear export of the AR even under androgen-deprived conditions. Moreover, the ability of C4-2 and LNCaP-SSR cells to grow in the absence of androgens was diminished after pharmacological inhibition of GSK-3β in vitro. The ability of SB216763 to modulate AR signalling and function in CRPC in vivo was additionally demonstrated in a modified chick chorioallantoic membrane xenograft assay after systemic delivery of SB216763. Our data suggest that inhibition of GSK-3β helps target the AR for export from the nucleus thereby diminishing the effects of mislocated AR in CRPC cells. Therefore, inhibition of GSK-3β could be an interesting new strategy for the treatment of CRPC.

Tumor Heterogeneity and Drug Resistance

International Nuclear Information System (INIS)

Kucerova, L.; Skolekova, S.; Kozovska, Z.

2015-01-01

New generation of sequencing methodologies revealed unexpected complexity and genomic alterations linked with the tumor subtypes. This diversity exists across the tumor types, histologic tumor subtypes and subsets of the tumor cells within the same tumor. This phenomenon is termed tumor heterogeneity. Regardless of its origin and mechanisms of development it has a major impact in the clinical setting. Genetic, phenotypic and expression pattern diversity of tumors plays critical role in the selection of suitable treatment and also in the prognosis prediction. Intratumoral heterogeneity plays a key role in the intrinsic and acquired chemoresistance to cytotoxic and targeted therapies. In this review we focus on the mechanisms of intratumoral and inter tumoral heterogeneity and their relationship to the drug resistance. Understanding of the mechanisms and spatiotemporal dynamics of tumor heterogeneity development before and during the therapy is important for the ability to design individual treatment protocols suitable in the given molecular context. (author)

Epigenetic markers in circulating cell-free DNA as prognostic markers for survival of castration-resistant prostate cancer patients.

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Hendriks, Rianne J; Dijkstra, Siebren; Smit, Frank P; Vandersmissen, Johan; Van de Voorde, Hendrik; Mulders, Peter F A; van Oort, Inge M; Van Criekinge, Wim; Schalken, Jack A

2018-04-01

Noninvasive biomarkers to guide personalized treatment for castration-resistant prostate cancer (CRPC) are needed. In this study, we analyzed hypermethylation patterns of two genes (GSTP1 and APC) in plasma cell-free DNA (cfDNA) of CRPC patients. The aim of this study was to analyze the cfDNA concentrations and levels of the epigenetic markers and to assess the value of these biomarkers for prognosis. In this prospective study, patients were included before starting new treatment after developing CRPC. The blood samples were collected prior to start of the treatment and at three time points thereafter. cfDNA was extracted from 1.5 mL of plasma and before performing a methylation-specific PCR, bisulfate modification was carried out. The median levels of cfDNA, GSTP1, and APC copies in the baseline samples of CRPC patients (n = 47) were higher than in controls (n = 30). In the survival analysis, the group with baseline marker levels below median had significant less PCa-related deaths (P-values Prostate Published by Wiley Periodicals, Inc.

Treatment Resistance Mechanisms of Malignant Glioma Tumor Stem Cells

International Nuclear Information System (INIS)

Schmalz, Philip G.R.; Shen, Michael J.; Park, John K.

2011-01-01

Malignant gliomas are highly lethal because of their resistance to conventional treatments. Recent evidence suggests that a minor subpopulation of cells with stem cell properties reside within these tumors. These tumor stem cells are more resistant to radiation and chemotherapies than their counterpart differentiated tumor cells and may underlie the persistence and recurrence of tumors following treatment. The various mechanisms by which tumor stem cells avoid or repair the damaging effects of cancer therapies are discussed

DBC1 promotes castration-resistant prostate cancer by positively regulating DNA binding and stability of AR-V7.

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Moon, Sue Jin; Jeong, Byong Chang; Kim, Hwa Jin; Lim, Joung Eun; Kwon, Ghee Young; Kim, Jeong Hoon

2018-03-01

Constitutively active AR-V7, one of the major androgen receptor (AR) splice variants lacking the ligand-binding domain, plays a key role in the development of castration-resistant prostate cancer (CRPC) and anti-androgen resistance. However, our understanding of the regulatory mechanisms of AR-V7-driven transcription is limited. Here we report DBC1 as a key regulator of AR-V7 transcriptional activity and stability in CRPC cells. DBC1 functions as a coactivator for AR-V7 and is required for the expression of AR-V7 target genes including CDH2, a mesenchymal marker linked to CRPC progression. DBC1 is required for recruitment of AR-V7 to its target enhancers and for long-range chromatin looping between the CDH2 enhancer and promoter. Mechanistically, DBC1 enhances DNA-binding activity of AR-V7 by direct interaction and inhibits CHIP E3 ligase-mediated ubiquitination and degradation of AR-V7 by competing with CHIP for AR-V7 binding, thereby stabilizing and activating AR-V7. Importantly, DBC1 depletion suppresses the tumorigenic and metastatic properties of CRPC cells. Our results firmly establish DBC1 as a critical AR-V7 coactivator that plays a key role in the regulation of DNA binding and stability of AR-V7 and has an important physiological role in CRPC progression.

An interesting experience of radiation castration in a patient of advanced breast carcinoma

International Nuclear Information System (INIS)

Matsubara, Sho; Suzuki, Hitoshi; Mine, Hiroko; Maeda, Manabu; Shibuya, Hitoshi

1980-01-01

Castration by irradiation was attempted in a patient with advanced breast cancer. Although a dose of irradiation sufficient for castration was given through the field usually used radiation castration, neither cessation of menstruation nor decrease in serum estradiol value could be observed. The subsequent hysteosalpingography revealed that the markedly malpositioned bilateral ovaries were not included within the beam of radiation. The field of irradiation to the malpositioned ovaries was determined based upon the hysterosalpingographic finding and a dose of 1,200 rad to the ovaries resulted in reduction of serum estradiol value in such a degree as surgical castration. (author)

Hepatic transcriptional changes in critical genes for gluconeogenesis following castration of bulls.

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Fassah, Dilla Mareistia; Jeong, Jin Young; Baik, Myunggi

2018-04-01

This study was performed to understand transcriptional changes in the genes involved in gluconeogenesis and glycolysis pathways following castration of bulls. Twenty Korean bulls were weaned at average 3 months of age, and castrated at 6 months. Liver tissues were collected from bulls (n = 10) and steers (n = 10) of Korean cattle, and hepatic gene expression levels were measured using quantitative real-time polymerase chain reaction. We examined hepatic transcription levels of genes encoding enzymes for irreversible reactions in both gluconeogenesis and glycolysis as well as genes encoding enzymes for the utilization of several glucogenic substrates. Correlations between hepatic gene expression and carcass characteristics were performed to understand their associations. Castration increased the mRNA (3.6 fold; pcastration. Castration increased mRNA levels of both lactate dehydrogenase A (1.5 fold; pCastration increased mRNA levels of glycerol kinase (2.7 fold; pCastration also increased mRNA levels of propionyl-CoA carboxylase beta (mitochondrial) (3.5 fold; pCastration increases transcription levels of critical genes coding for enzymes involved in irreversible gluconeogenesis reactions from pyruvate to glucose and enzymes responsible for incorporation of glucogenic substrates including lactate, glycerol, and propionate. Hepatic gluconeogenic gene expression levels were associated with intramuscular fat deposition.

Non-Coding RNAs in Castration-Resistant Prostate Cancer: Regulation of Androgen Receptor Signaling and Cancer Metabolism.

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Shih, Jing-Wen; Wang, Ling-Yu; Hung, Chiu-Lien; Kung, Hsing-Jien; Hsieh, Chia-Ling

2015-12-04

Hormone-refractory prostate cancer frequently relapses from therapy and inevitably progresses to a bone-metastatic status with no cure. Understanding of the molecular mechanisms conferring resistance to androgen deprivation therapy has the potential to lead to the discovery of novel therapeutic targets for type of prostate cancer with poor prognosis. Progression to castration-resistant prostate cancer (CRPC) is characterized by aberrant androgen receptor (AR) expression and persistent AR signaling activity. Alterations in metabolic activity regulated by oncogenic pathways, such as c-Myc, were found to promote prostate cancer growth during the development of CRPC. Non-coding RNAs represent a diverse family of regulatory transcripts that drive tumorigenesis of prostate cancer and various other cancers by their hyperactivity or diminished function. A number of studies have examined differentially expressed non-coding RNAs in each stage of prostate cancer. Herein, we highlight the emerging impacts of microRNAs and long non-coding RNAs linked to reactivation of the AR signaling axis and reprogramming of the cellular metabolism in prostate cancer. The translational implications of non-coding RNA research for developing new biomarkers and therapeutic strategies for CRPC are also discussed.

Meat quality of castrated and non-castrated Santa Ines lambs subjected to food restriction

Directory of Open Access Journals (Sweden)

Dayanne Lima de Sousa

2016-06-01

Full Text Available This study aimed to evaluate the quality of meat of castrated and non-castrated Santa Ines lambs submitted to food restriction. Were used 30 lambs, 15 castrated and 15 non-castrated, about two months of age and average initial body weight of 13.00 ± 1.49 kg. The lambs were distributed in a completely randomized design in a factorial arrangement 3 x 2 (restriction level x sex class, according to the amount of food provided. The duration of the experiment was determined by the time required for the animals in the one of the groups achieved 28 kg of body weight. There was interaction between food restriction levels and sex class to the variables intensity of yellow color and pH in the longissimus lumborum muscle and the shear force in the semimembranosus muscle. In non-castrated animals, the intensity of yellow color was higher in the longissimus lumborum muscle at the level of 30% of food restriction. There was no significant interaction between food restriction levels and sex class for the quality aspects related to color saturation, color tone, luminosity, red intensity, water holding capacity and cooking losses in longissimus lumborum and semimembranosus muscles. Although food restriction and sex class have influenced the variables related to the quality of meat of the animals evaluated, the mean values are considered acceptable by the literature. The feeding restriction levels and sex class influence some important features of quality of Santa Ines lamb meat.

Symptoms and Impacts in Non-Metastatic Castration-Resistant Prostate Cancer: Qualitative Study Findings.

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Tomaszewski, Erin L; Moise, Pierre; Krupnick, Robert N; Downing, Jared; Meyer, Margaret; Naidoo, Shevani; Holmstrom, Stefan

2017-10-01

We developed a conceptual model to define key concepts associated with patients' experiences with the signs, symptoms, and impacts of non-metastatic castration-resistant prostate cancer (M0-CRPC). A targeted review of peer-reviewed literature, and other publicly available information, identified and categorized symptoms and impacts related to early-stage prostate cancer. Semi-structured interviews with five clinical experts helped determine the most relevant and important concepts for patients with M0-CRPC. Qualitative interviews with 17 patients with M0-CRPC identified the most frequently experienced symptoms and impacts, and their degree of interference with patients' lives. The findings from these three lines of evidence were summarized in a conceptual model. Literature searches identified mainly urinary, intestinal, and sexual symptoms. Experts noted the symptoms most frequently mentioned by patients include erectile dysfunction, loss of sexual desire or interest, incontinence/leaking, urgency, and hot flashes. Patient interviews confirmed the high frequency of erectile dysfunction, loss of libido, urinary urgency, and incontinence. The most frequently mentioned impacts expressed by patients were the need to monitor/plan for urinary frequency, interference with/restriction of daily activities, and frustration or anxiety over diagnosis, symptoms, or treatment. Symptoms and impacts most frequently experienced by patients were typically not those with the greatest effects on their lives; rather, those with the greatest consequences were related to treatment. The leading concerns associated with M0-CRPC were related to voiding and sexual dysfunction. The most relevant symptoms and impacts expressed by patients may be a consequence of therapy rather than of the disease.

Challenges in the sequencing of therapies for the management of metastatic castration-resistant prostate cancer.

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Parente, Phillip; Parnis, Francis; Gurney, Howard

2014-09-01

Prior to 2010, docetaxel was the standard option for chemotherapy in men with metastatic castration-resistant prostate cancer (mCRPC). Today, the picture is vastly different: several additional therapies have each demonstrated a survival benefit such that we now have chemotherapy (cabazitaxel), androgen suppressive agents (abiraterone acetate and enzalutamide), a cellular vaccine (sipuleucel-T) and radium-233 (for symptomatic bone metastases). With several other agents in the pipeline for late-stage disease, the future looks promising for mCRPC. As the available data are not able to inform as to the optimum sequencing of therapy, this remains a challenge. This paper draws on insights from published and ongoing clinical studies to provide a practical patient-focused approach to maximize the benefits of the current therapeutic armamentarium. Preliminary sequencing suggestions are made based on clinical trial criteria. But until more data become available, clinical gestalt, experience, cost and individual patient preferences will continue to drive choices. © 2014 Wiley Publishing Asia Pty Ltd.

[14C]Fluciclovine (alias anti-[14C]FACBC) uptake and ASCT2 expression in castration-resistant prostate cancer cells

International Nuclear Information System (INIS)

Ono, Masahiro; Oka, Shuntaro; Okudaira, Hiroyuki; Nakanishi, Takeo; Mizokami, Atsushi; Kobayashi, Masato; Schuster, David M.; Goodman, Mark M.; Shirakami, Yoshifumi; Kawai, Keiichi

2015-01-01

Introduction: trans-1-Amino-3-[ 18 F]fluorocyclobutanecarboxylic acid ([ 18 F]fluciclovine, also known as anti-[ 18 F]FACBC), is a tracer for positron emission tomography (PET) imaging for detection of tumors such as prostate cancer (PCa). Our previous study showed that ASCT2 (Na + -dependent amino acid transporter (AAT)) mediates fluciclovine uptake in androgen-dependent PCa cells; its expression is influenced by androgen, a key hormone in the progression of primary PCa and castration-resistant prostate cancer (CRPC). In this study, we investigated the uptake mechanisms and feasibility of [ 18 F]fluciclovine for CRPC in the androgen-dependent PCa cell line LNCaP and LNCaP-derivatives LNCaP-SF and LN-REC4. Methods: LNCaP-SF was established after long-term cultivation of LNCaP in steroid-free conditions, and LN-Pre and LN-REC4 were established from LNCaP inoculated in intact and castrated severe combined immunodeficient mice, respectively. Uptake and competitive inhibition experiments were performed with trans-1-amino-3-fluoro[1- 14 C]cyclobutanecarboxylic acid ([ 14 C]fluciclovine) to characterize the involvement of AATs in androgen-dependent PCa (LNCaP and LN-Pre) and CRPC-like (LNCaP-SF and LN-REC4) cell lines. AAT expression was analyzed by Western blotting, and [ 14 C]fluciclovine uptake in androgen-dependent PCa and CRPC-like cell lines were investigated in the presence or absence of dihydrotestosterone (DHT). Results: The contribution of Na + -dependent AATs to [ 14 C]fluciclovine uptake in all cell lines was 88−98%, and [ 14 C]fluciclovine uptake was strongly inhibited by L-glutamine and L-serine, the substrates for Na + -dependent alanine-serine-cysteine (system ASC) AATs, in the presence of Na + . DHT enhanced ASCT2 expression in LNCaP, LN-Pre, and LN-REC4, but not in LNCaP-SF, and the responses of ASCT2 expression to DHT correlated with [ 14 C]fluciclovine uptake. Conclusions: System ASC, especially ASCT2, could play a major role in [ 14 C

Lymphocyte function following radium-223 therapy in patients with metastasized, castration-resistant prostate cancer

International Nuclear Information System (INIS)

Barsegian, Vahe; Moeckel, Daniel; Mueller, Stefan P.; Bockisch, Andreas; Horn, Peter A.; Lindemann, Monika

2017-01-01

Therapy with the alpha-emitter radium-223 chloride ("2"2"3Ra) is an innovative therapeutic option in patients with metastasized, castration-resistant prostate cancer. However, radiotherapy can lead to hematopoietic toxicity. The aim of this study was to determine if "2"2"3Ra therapy induces an impairment of cellular antimicrobial immune responses. In 11 patients receiving "2"2"3Ra treatment, lymphocyte proliferation and the production of pro- and anti-inflammatory cytokines (interferon-γ and interleukin-10) were determined, using lymphocyte transformation testing and ELISpot, respectively. Lymphocyte function after stimulation with mitogens and microbial antigens was assessed prior to therapy and at day 1, 7 and 28 after therapy. Lymphocyte proliferation and the production of interferon-γ and interleukin-10 towards mitogens and antigens remained unchanged after therapy. Consistent with these in vitro data, we did not observe infectious complications after treatment. The results argue against an impairment of lymphocyte function after "2"2"3Ra therapy. Thus, immune responses against pathogens should remain unaffected. (orig.)

Efficacy and safety of enzalutamide in patients 75 years or older with chemotherapy-naive metastatic castration-resistant prostate cancer

DEFF Research Database (Denmark)

Graff, J N; Baciarello, G; Armstrong, A J

2016-01-01

BACKGROUND: Prostate cancer disproportionately affects older men. Because age affects treatment decisions, it is important to understand the efficacy and tolerability of therapies for advanced prostate cancer in elderly men. This analysis describes efficacy and safety outcomes in men aged ≥75 years......-resistant prostate cancer. Overall survival (OS) and radiographic progression-free survival (rPFS) were coprimary end points. Subgroup analysis of men aged ≥75 years (elderly) and men aged ... who received enzalutamide, an androgen receptor inhibitor, in the phase III PREVAIL trial. PATIENTS AND METHODS: PREVAIL was a randomised, double-blind, multinational study of oral enzalutamide 160 mg/day (N = 872) versus placebo (N = 845) in chemotherapy-naive men with metastatic castration...

Antiproliferative activity of novel imidazopyridine derivatives on castration-resistant human prostate cancer cells.

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Muniyan, Sakthivel; Chou, Yu-Wei; Ingersoll, Matthew A; Devine, Alexus; Morris, Marisha; Odero-Marah, Valerie A; Khan, Shafiq A; Chaney, William G; Bu, Xiu R; Lin, Ming-Fong

2014-10-10

Metastatic prostate cancer (mPCa) relapses after a short period of androgen deprivation therapy and becomes the castration-resistant prostate cancer (CR PCa); to which the treatment is limited. Hence, it is imperative to identify novel therapeutic agents towards this patient population. In the present study, antiproliferative activities of novel imidazopyridines were compared. Among three derivatives, PHE, AMD and AMN, examined, AMD showed the highest inhibitory activity on LNCaP C-81 cell proliferation, following dose- and time-dependent manner. Additionally, AMD exhibited significant antiproliferative effect against a panel of PCa cells, but not normal prostate epithelial cells. Further, when compared to AMD, its derivative DME showed higher inhibitory activities on PCa cell proliferation, clonogenic potential and in vitro tumorigenicity. The inhibitory activity was apparently in part due to the induction of apoptosis. Mechanistic studies indicate that AMD and DME treatments inhibited both AR and PI3K/Akt signaling. The results suggest that better understanding of inhibitory mechanisms of AMD and DME could help design novel therapeutic agents for improving the treatment of CR PCa. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Prediction of overall survival for patients with metastatic castration-resistant prostate cancer: development of a prognostic model through a crowdsourced challenge with open clinical trial data.

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Guinney, Justin; Wang, Tao; Laajala, Teemu D; Winner, Kimberly Kanigel; Bare, J Christopher; Neto, Elias Chaibub; Khan, Suleiman A; Peddinti, Gopal; Airola, Antti; Pahikkala, Tapio; Mirtti, Tuomas; Yu, Thomas; Bot, Brian M; Shen, Liji; Abdallah, Kald; Norman, Thea; Friend, Stephen; Stolovitzky, Gustavo; Soule, Howard; Sweeney, Christopher J; Ryan, Charles J; Scher, Howard I; Sartor, Oliver; Xie, Yang; Aittokallio, Tero; Zhou, Fang Liz; Costello, James C

2017-01-01

Improvements to prognostic models in metastatic castration-resistant prostate cancer have the potential to augment clinical trial design and guide treatment strategies. In partnership with Project Data Sphere, a not-for-profit initiative allowing data from cancer clinical trials to be shared broadly with researchers, we designed an open-data, crowdsourced, DREAM (Dialogue for Reverse Engineering Assessments and Methods) challenge to not only identify a better prognostic model for prediction of survival in patients with metastatic castration-resistant prostate cancer but also engage a community of international data scientists to study this disease. Data from the comparator arms of four phase 3 clinical trials in first-line metastatic castration-resistant prostate cancer were obtained from Project Data Sphere, comprising 476 patients treated with docetaxel and prednisone from the ASCENT2 trial, 526 patients treated with docetaxel, prednisone, and placebo in the MAINSAIL trial, 598 patients treated with docetaxel, prednisone or prednisolone, and placebo in the VENICE trial, and 470 patients treated with docetaxel and placebo in the ENTHUSE 33 trial. Datasets consisting of more than 150 clinical variables were curated centrally, including demographics, laboratory values, medical history, lesion sites, and previous treatments. Data from ASCENT2, MAINSAIL, and VENICE were released publicly to be used as training data to predict the outcome of interest-namely, overall survival. Clinical data were also released for ENTHUSE 33, but data for outcome variables (overall survival and event status) were hidden from the challenge participants so that ENTHUSE 33 could be used for independent validation. Methods were evaluated using the integrated time-dependent area under the curve (iAUC). The reference model, based on eight clinical variables and a penalised Cox proportional-hazards model, was used to compare method performance. Further validation was done using data from a

PSMA-Based Radioligand Therapy for Metastatic Castration-Resistant Prostate Cancer: The Bad Berka Experience Since 2013.

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Kulkarni, Harshad R; Singh, Aviral; Schuchardt, Christiane; Niepsch, Karin; Sayeg, Manal; Leshch, Yevgeniy; Wester, Hans-Juergen; Baum, Richard P

2016-10-01

A potential milestone in personalized nuclear medicine is theranostics of metastatic castration-resistant prostate cancer (mCRPC) based on molecular imaging using PET/CT with 68 Ga-labeled prostate-specific membrane antigen (PSMA) ligands and molecular radiotherapy using PSMA-targeted radioligand therapy (PRLT) with 177 Lu-PSMA ligands. 68 Ga-PSMA PET/CT enables accurate detection of mCRPC lesions with high diagnostic sensitivity and specificity and provides quantitative and reproducible data that can be used to select patients for PRLT and therapeutic monitoring. Our comprehensive experience over the last 3 years using different radioligands indicates that PRLT is highly effective for the treatment of mCRPC, even in advanced cases, and potentially lends a significant benefit to overall and progression-free survival. Additionally, significant improvement in clinical symptoms and excellent palliation of pain can be achieved. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Aflibercept versus placebo in combination with docetaxel and prednisone for treatment of men with metastatic castration-resistant prostate cancer (VENICE): a phase 3, double-blind randomised trial.

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Tannock, Ian F; Fizazi, Karim; Ivanov, Sergey; Karlsson, Camilla Thellenberg; Fléchon, Aude; Skoneczna, Iwona; Orlandi, Francisco; Gravis, Gwenaelle; Matveev, Vsevolod; Bavbek, Sevil; Gil, Thierry; Viana, Luciano; Arén, Osvaldo; Karyakin, Oleg; Elliott, Tony; Birtle, Alison; Magherini, Emmanuelle; Hatteville, Laurence; Petrylak, Daniel; Tombal, Bertrand; Rosenthal, Mark

2013-07-01

Docetaxel plus prednisone is standard first-line chemotherapy for men with metastatic castrate-resistant prostate cancer. Aflibercept is a recombinant human fusion protein that binds A and B isoforms of VEGF and placental growth factor, thereby inhibiting angiogenesis. We assessed whether the addition of aflibercept to docetaxel and prednisone would improve overall survival in men with metastatic castrate-resistant prostate cancer compared with the addition of placebo to docetaxel and prednisone. VENICE was a phase 3, multicentre, randomised double-blind placebo-controlled parallel group study done in 31 countries (187 sites). Men with metastatic castrate-resistant prostate cancer, adequate organ function, and no prior chemotherapy were treated with docetaxel (75 mg/m(2) intravenously every 3 weeks) and oral prednisone (5 mg twice daily) and randomly allocated (1:1) to receive aflibercept (6 mg/kg) or placebo, intravenously, every 3 weeks. Treatment allocation was done centrally via an interactive voice response system, using a computer-generated sequence with a permuted-block size of four and stratified according Eastern Co-operative Group performance status (0-1 vs 2). Patients, investigators, and other individuals responsible for study conduct and data analysis were masked to treatment assignment. Aflibercept or placebo vials were supplied in identical boxes. The primary endpoint was overall survival using intention-to-treat analysis. This is the primary analysis of the completed trial. The study is registered with ClinicalTrials.gov, number NCT00519285 FINDINGS: Between Aug 17, 2007, and Feb 11, 2010, 1224 men were randomly allocated to treatment: 612 to each group. At final analysis, median follow-up was 35 months (IQR 29-41) and 873 men had died. Median overall survival was 22·1 months (95·6% CI 20·3-24·1) in the aflibercept group and 21·2 months (19·6-23·8) in the placebo group (stratified hazard ratio 0·94, 95·6% CI 0·82-1·08; p=0·38). We

Improvement of a predictive model of castration-resistant prostate cancer: functional genetic variants in TGFβ1 signaling pathway modulation.

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Ana L Teixeira

Full Text Available Prostate cancer (PC is the most frequently diagnosed cancer in men. The acquisition of castration-resistant (CR phenotype is associated with the activation of signaling pathways mediated by growth factors. The TGFβ1 and its receptors have an important role in tumor progression, being the pro-apoptotic function modulated by the expression of TGFBR2. A single nucleotide polymorphism -875 G > A in TGFBR2 gene has been described, which may influence the expression levels of the receptor. Our purpose was to investigate the potential role of TGFBR2-875G>A in PC risk and in the response to androgen deprivation therapy (ADT. TGFBR2-875G>A polymorphism was studied by allelic discrimination using real-time polymerase chain reaction (PCR in 891 patients with PC and 874 controls. A follow-up study was undertaken to evaluate response to ADT. The TGFBR2 and SMAD7 mRNA expression were analyzed by a quantitative real-time PCR. We found that TGFBR2-875GG homozygous patients present lower expression levels of TGFBR2 mRNA (AA/AG: 2(-ΔΔCT =1.5, P=0.016. GG genotype was also associated with higher Gleason grade (OR=1.51, P=0.019 and increased risk of an early relapse after ADT (HR=1.47, P=0.024. The concordance (c index analysis showed that the definition of profiles that contains information regarding tumor characteristics associated with genetic information present an increased capacity to predict the risk for CR development (c-index model 1: 0.683 vs model 2: 0.736 vs model 3: 0.746 vs model 4: 0.759. The TGFBR2-875G>A contribution to an early relapse in ADT patients, due to changes in mRNA expression, supports the involvement of TGFβ1 pathway in CRPC. Furthermore, according to our results, we hypothesize the potential benefits of the association of genetic information in predictive models of CR development.

Nanoparticle-mediated combination chemotherapy and photodynamic therapy overcomes tumor drug resistance.

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Khdair, Ayman; Chen, Di; Patil, Yogesh; Ma, Linan; Dou, Q Ping; Shekhar, Malathy P V; Panyam, Jayanth

2010-01-25

Tumor drug resistance significantly limits the success of chemotherapy in the clinic. Tumor cells utilize multiple mechanisms to prevent the accumulation of anticancer drugs at their intracellular site of action. In this study, we investigated the anticancer efficacy of doxorubicin in combination with photodynamic therapy using methylene blue in a drug-resistant mouse tumor model. Surfactant-polymer hybrid nanoparticles formulated using an anionic surfactant, Aerosol-OT (AOT), and a naturally occurring polysaccharide polymer, sodium alginate, were used for synchronized delivery of the two drugs. Balb/c mice bearing syngeneic JC tumors (mammary adenocarcinoma) were used as a drug-resistant tumor model. Nanoparticle-mediated combination therapy significantly inhibited tumor growth and improved animal survival. Nanoparticle-mediated combination treatment resulted in enhanced tumor accumulation of both doxorubicin and methylene blue, significant inhibition of tumor cell proliferation, and increased induction of apoptosis. These data suggest that nanoparticle-mediated combination chemotherapy and photodynamic therapy using doxorubicin and methylene blue has significant therapeutic potential against drug-resistant tumors. Copyright 2009 Elsevier B.V. All rights reserved.

The welfare significance of the castration of cattle: a review.

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Stafford, K J; Mellor, D J

2005-10-01

Castration is an ancient husbandry procedure used to produce docile cattle for draught work, to reduce unwanted breeding, and to modify carcass quality. All the physical methods used to castrate cattle have side-effects and cause pain. The plasma cortisol response to castration using Burdizzo clamps and, by inference, the acute pain experienced, is less than that caused by surgical, rubber-ring or latex-band castration. The cortisol response may be influenced by the age of the animal castrated, but this has not been well defined. Local anaesthesia virtually eliminates the cortisol response, and thus the acute pain, caused by rubber-ring or latex-band castration, but needs to be combined with a systemic analgesic such as the non-steroidal anti-inflammatory drug ketoprofen to eliminate the cortisol response to Burdizzo or surgical castration. When used alone, ketoprofen sometimes reduces the cortisol response to Burdizzo or surgical castration but may need to be accompanied by local anaesthesia to eliminate the pain-induced behaviour seen during the castration process itself. Thus, pharmacological methods are available to virtually eliminate the acute pain experienced by calves during the 12 h following castration. The use of these methods is an additional cost for farmers and may be limited by the availability of drugs for farmers to use and the scarcity of veterinarians in farm animal practice.

Reflections on the therapeutic use of 223RaCl2 for bone metastases resulting from prostate cancer resistant to castration

International Nuclear Information System (INIS)

Astudillo V, A. J.; Paredes G, L.

2015-10-01

In January 2014 the Comision Federal para la Proteccion contra Riesgos Sanitarios of the Ministry of Health in Mexico, authorize the use of 223 RaCl 2 as the first radiopharmaceutical emitter α for therapeutic purposes in cases of bone metastases resulting from prostate cancer resistant to castration. The paper analyzes the main variables that affect the metrological traceability using activity meters to evaluate the gamma activity of 223 RaCl 2 in hospitals, because it has a chain of complex decay with alpha, beta and gamma emitters, so was important to verify if a gamma activity measurement for a multiple emitter is reliable to determine the total alpha absorbed dose to bone in a patient. (Author)

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.

Effect of intravenous sodium salicylate administration prior to castration on plasma cortisol and electroencephalography parameters in calves.

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Bergamasco, L; Coetzee, J F; Gehring, R; Murray, L; Song, T; Mosher, R A

2011-12-01

Nociception is an unavoidable consequence of many routine management procedures such as castration in cattle. This study investigated electroencephalography (EEG) parameters and cortisol levels in calves receiving intravenous sodium salicylate in response to a castration model. Twelve Holstein calves were randomly assigned to the following groups: (i) castrated, untreated controls, (ii) 50 mg/kg sodium salicylate IV precastration, were blood sampled at 0, 5, 10, 20, 30, 45, 60, 90, 120, 150, 180, 240, 360, and 480 min postcastration. The EEG recording included baseline, castration, immediate recovery (0-5 min after castration), middle recovery (5-10 min after castration), and late recovery (10-20 min after castration). Samples were analyzed by competitive chemiluminescent immunoassay and fluorescence polarization immunoassay for cortisol and salicylate, respectively. EEG visual inspection and spectral analysis were performed. Statistical analyses included anova repeated measures and correlations between response variable. No treatment effect was noted between the two groups for cortisol and EEG measurements, namely an attenuation of acute cortisol response and EEG desynchronization in sodium salicylate group. Time effects were noted for EEG measurements, cortisol and salicylates levels. Significant correlations between cortisol and EEG parameters were noted. These findings have implications for designing effective analgesic regimens, and they suggest that EEG can be useful to monitor pain attributable to castration. © 2011 Blackwell Publishing Ltd.

Effects of castration on expression of lipid metabolism genes in the liver of korean cattle.

Science.gov (United States)

Baik, Myunggi; Nguyen, Trang Hoa; Jeong, Jin Young; Piao, Min Yu; Kang, Hyeok Joong

2015-01-01

Castration induces the accumulation of body fat and deposition of intramuscular fat in Korean cattle, resulting in improved beef quality. However, little is known about the metabolic adaptations in the liver following castration. To understand changes in lipid metabolism following castration, hepatic expression levels of lipid metabolism genes were compared between Korean bulls and steers. Steers had higher (pcastration of bulls. However, we found no differences in the hepatic expression levels of genes related to triglyceride synthesis (mitochondrial glycerol-3-phosphate acyltransferase, diacylglycerol O-acyltransferase 1 and 2) and fatty acid (FA) oxidation (carnitine palmitoyltransferase 1A, C-4 to C-12 straight chain acyl-CoA dehydrogenase, very long chain acyl-CoA dehydrogenase) between bulls and steers. No differences in gene expression for very-low-density lipoprotein (VLDL) secretion, including apolipoprotein B mRNA and microsomal triglyceride transfer protein (MTTP) protein, were observed in the liver although MTTP mRNA levels were higher in steers compared to bulls. In conclusion, FA synthesis may contribute to increased hepatic lipid deposition in steers following castration. However, hepatic lipid metabolism, including triglyceride synthesis, FA oxidation, and VLDL secretion, was not significantly altered by castration. Our results suggest that hepatic lipid metabolism does not significantly contribute to increased body fat deposition in steers following castration.

Detection of AR-V7 mRNA in whole blood may not predict the effectiveness of novel endocrine drugs for castration-resistant prostate cancer.

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Takeuchi, Takumi; Okuno, Yumiko; Hattori-Kato, Mami; Zaitsu, Masayoshi; Mikami, Koji

2016-01-01

A splice variant of androgen receptor (AR), AR-V7, lacks in androgen-binding portion and leads to aggressive cancer characteristics. Reverse transcription-polymerase chain reactions (PCRs) and subsequent nested PCRs for the amplification of AR-V7 and prostate-specific antigen (PSA) transcripts were done for whole blood of patients with prostate cancer and male controls. With primary reverse transcription PCRs, AR-V7 and PSA were detected in 4.5% and 4.7% of prostate cancer, respectively. With nested PCRs, AR-V7 messenger RNA (mRNA) was positive in 43.8% of castration-sensitive prostate cancer and 48.1% of castration-resistant prostate cancer (CRPC), while PSA mRNA was positive in 6.3% of castration-sensitive prostate cancer and 18.5% of CRPC. Whole-blood samples of controls showed AR-V7 mRNA expression by nested PCR. Based on multivariate analysis, expression of AR-V7 mRNA in whole blood was not significantly correlated with clinical parameters and PSA mRNA in blood, while univariate analysis showed a correlation between AR-V7 mRNA and metastasis at initial diagnosis. Detection of AR-V7 mRNA did not predict the reduction of serum PSA in patients with CRPC following abiraterone and enzalutamide administration. In conclusion, AR-V7 mRNA expression in normal hematopoietic cells may have annihilated the manifestation of aggressiveness of prostate cancer and the prediction of the effectiveness of abiraterone and enzalutamide by the assessment of AR-V7 mRNA in blood.

Cisplatin Resistant Spheroids Model Clinically Relevant Survival Mechanisms in Ovarian Tumors.

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Winyoo Chowanadisai

Full Text Available The majority of ovarian tumors eventually recur in a drug resistant form. Using cisplatin sensitive and resistant cell lines assembled into 3D spheroids we profiled gene expression and identified candidate mechanisms and biological pathways associated with cisplatin resistance. OVCAR-8 human ovarian carcinoma cells were exposed to sub-lethal concentrations of cisplatin to create a matched cisplatin-resistant cell line, OVCAR-8R. Genome-wide gene expression profiling of sensitive and resistant ovarian cancer spheroids identified 3,331 significantly differentially expressed probesets coding for 3,139 distinct protein-coding genes (Fc >2, FDR < 0.05 (S2 Table. Despite significant expression changes in some transporters including MDR1, cisplatin resistance was not associated with differences in intracellular cisplatin concentration. Cisplatin resistant cells were significantly enriched for a mesenchymal gene expression signature. OVCAR-8R resistance derived gene sets were significantly more biased to patients with shorter survival. From the most differentially expressed genes, we derived a 17-gene expression signature that identifies ovarian cancer patients with shorter overall survival in three independent datasets. We propose that the use of cisplatin resistant cell lines in 3D spheroid models is a viable approach to gain insight into resistance mechanisms relevant to ovarian tumors in patients. Our data support the emerging concept that ovarian cancers can acquire drug resistance through an epithelial-to-mesenchymal transition.

Hepatic transcriptional changes in critical genes for gluconeogenesis following castration of bulls

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Dilla Mareistia Fassah

2018-04-01

Full Text Available Objective This study was performed to understand transcriptional changes in the genes involved in gluconeogenesis and glycolysis pathways following castration of bulls. Methods Twenty Korean bulls were weaned at average 3 months of age, and castrated at 6 months. Liver tissues were collected from bulls (n = 10 and steers (n = 10 of Korean cattle, and hepatic gene expression levels were measured using quantitative real-time polymerase chain reaction. We examined hepatic transcription levels of genes encoding enzymes for irreversible reactions in both gluconeogenesis and glycolysis as well as genes encoding enzymes for the utilization of several glucogenic substrates. Correlations between hepatic gene expression and carcass characteristics were performed to understand their associations. Results Castration increased the mRNA (3.6 fold; p<0.01 and protein levels (1.4 fold; p< 0.05 of pyruvate carboxylase and mitochondrial phosphoenolpyruvate carboxykinase genes (1.7 fold; p<0.05. Hepatic mRNA levels of genes encoding the glycolysis enzymes were not changed by castration. Castration increased mRNA levels of both lactate dehydrogenase A (1.5 fold; p<0.05 and lactate dehydrogenase B (2.2 fold; p<0.01 genes for lactate utilization. Castration increased mRNA levels of glycerol kinase (2.7 fold; p<0.05 and glycerol-3-phosphate dehydrogenase 1 (1.5 fold; p<0.05 genes for glycerol utilization. Castration also increased mRNA levels of propionyl-CoA carboxylase beta (mitochondrial (3.5 fold; p<0.01 and acyl-CoA synthetase short chain family member 3 (1.3 fold; p = 0.06 genes for propionate incorporation. Conclusion Castration increases transcription levels of critical genes coding for enzymes involved in irreversible gluconeogenesis reactions from pyruvate to glucose and enzymes responsible for incorporation of glucogenic substrates including lactate, glycerol, and propionate. Hepatic gluconeogenic gene expression levels were associated with intramuscular

Profile of apalutamide in the treatment of metastatic castration-resistant prostate cancer: evidence to date.

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Chong, Julio T; Oh, William K; Liaw, Bobby C

2018-01-01

Advances in therapies have led to the approval of six therapeutic agents since 2004, each demonstrating overall survival benefit in randomized studies, and these have significantly improved the outlook for men facing metastatic castration-resistant prostate cancer (CRPC). More recently, efforts have been directed at trying to effect change at earlier phases of the disease. Apalutamide (ARN-509), a second-generation androgen receptor antagonist, recently received approval in the nonmetastatic (M0) CRPC space. Similar to enzalutamide, apalutamide inhibits the binding of androgen to androgen receptor (AR), nuclear translocation of the androgen-AR complex, and binding of AR transcription complex to DNA-binding sites and transcription elements. Phase I and II trial experience demonstrates the safety and tolerability of apalutamide, as well as its efficacy in effecting prostate-specific antigen response and radiographic-free survival in CRPC. US Food and Drug Administration approval in M0 CRPC was granted following positive results from the phase III SPARTAN study, where apalutamide demonstrated significant improvements in metastasis-free survival and time to symptomatic progression as compared to placebo.

Acute Cold / Restraint Stress in Castrated Rats

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Farideh Zafari Zangeneh

2008-09-01

Full Text Available Objective: The present study aimed to determine whether castration altered osmotically stimulated vasopressin (VP release and urinary volume and what is the role of endocrine-stress axis in this process.Materials and methods: Totally 108 mice were studied in two main groups of castrated (n=78 and control (n=30. Each group was extracted by acute cold stress (4◦C for 2h/day, restraint stress (by syringes 60cc 2h/day and cold/restraint stress. The castrated group was treated in sub groups of testosterone, control (sesame oil as vehicle of testosterone. Propranolol as blocker of sympathetic nervous system was given to both groups of castrated mice and main control.Results: Our results showed that, there is interactions between testosterone and sympathetic nervous system on vasopressin, because urine volume was decreased only in testoctomized mice with cold/restraint and cold stress (P<0.001; propranolol as the antagonist of sympathetic nervous system could block and increase urine volume in castrated mice. This increased volume of urine was due to acute cold stress, not restraint stress (p<0.001. The role of testosterone, noradrenalin (NA and Vasopressin (VP in the acute cold stress is confirmed, because testosterone could return the effect of decreased urine volume in control group (P<0.001. Conclusion: Considering the effect of cold/restraint stress on urinary volume in castrated mice shows that there is interaction between sex hormone (testosterone, vasopressin and adrenergic systems.

Down-regulation of HSP27 sensitizes TRAIL-resistant tumor cell to TRAIL-induced apoptosis

DEFF Research Database (Denmark)

Zhuang, Hongqin; Jiang, Weiwei; Cheng, Wei

2010-01-01

Tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) has recently emerged as a cancer therapeutic agent because it preferentially induces apoptosis in human cancer over normal cells. Most tumor cells, including lung cancer cell line A549, unfortunately, are resistant to TRAIL tre...

The Stromal Contribution to the Development of Resistance to New Generation Drugs by Castrate Resistant Prostate Cancers

Science.gov (United States)

2016-05-01

and by further increasing their outputs of T and DHT . Finally, in Aim 3, I will attempt to demonstrate in cell co-culture models that Sonic Hh produced...of CRPC through their ability to synthesize T and DHT upon Hh stimulation from metastatic PCa cells, and whether this adaptation can increase...backdoor pathway, which bypasses testosterone (T) as an intermediate for dihydrotestosterone ( DHT ) (3, 9-11). 4 After ADT, recurrence as castration

Comparison of Timed Automata with Discrete Event Simulation for Modeling of Biomarker-Based Treatment Decisions: An Illustration for Metastatic Castration-Resistant Prostate Cancer.

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Degeling, Koen; Schivo, Stefano; Mehra, Niven; Koffijberg, Hendrik; Langerak, Rom; de Bono, Johann S; IJzerman, Maarten J

2017-12-01

With the advent of personalized medicine, the field of health economic modeling is being challenged and the use of patient-level dynamic modeling techniques might be required. To illustrate the usability of two such techniques, timed automata (TA) and discrete event simulation (DES), for modeling personalized treatment decisions. An early health technology assessment on the use of circulating tumor cells, compared with prostate-specific antigen and bone scintigraphy, to inform treatment decisions in metastatic castration-resistant prostate cancer was performed. Both modeling techniques were assessed quantitatively, in terms of intermediate outcomes (e.g., overtreatment) and health economic outcomes (e.g., net monetary benefit). Qualitatively, among others, model structure, agent interactions, data management (i.e., importing and exporting data), and model transparency were assessed. Both models yielded realistic and similar intermediate and health economic outcomes. Overtreatment was reduced by 6.99 and 7.02 weeks by applying circulating tumor cell as a response marker at a net monetary benefit of -€1033 and -€1104 for the TA model and the DES model, respectively. Software-specific differences were observed regarding data management features and the support for statistical distributions, which were considered better for the DES software. Regarding method-specific differences, interactions were modeled more straightforward using TA, benefiting from its compositional model structure. Both techniques prove suitable for modeling personalized treatment decisions, although DES would be preferred given the current software-specific limitations of TA. When these limitations are resolved, TA would be an interesting modeling alternative if interactions are key or its compositional structure is useful to manage multi-agent complex problems. Copyright © 2017 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights

Effects of Castration on Expression of Lipid Metabolism Genes in the Liver of Korean Cattle

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Myunggi Baik

2015-01-01

Full Text Available Castration induces the accumulation of body fat and deposition of intramuscular fat in Korean cattle, resulting in improved beef quality. However, little is known about the metabolic adaptations in the liver following castration. To understand changes in lipid metabolism following castration, hepatic expression levels of lipid metabolism genes were compared between Korean bulls and steers. Steers had higher (p<0.001 hepatic lipids contents and higher (p<0.01 mRNA levels of lipogenic acetyl-CoA carboxylase. This differential gene expression may, in part, contribute to increased hepatic lipid content following the castration of bulls. However, we found no differences in the hepatic expression levels of genes related to triglyceride synthesis (mitochondrial glycerol-3-phosphate acyltransferase, diacylglycerol O-acyltransferase 1 and 2 and fatty acid (FA oxidation (carnitine palmitoyltransferase 1A, C-4 to C-12 straight chain acyl-CoA dehydrogenase, very long chain acyl-CoA dehydrogenase between bulls and steers. No differences in gene expression for very-low-density lipoprotein (VLDL secretion, including apolipoprotein B mRNA and microsomal triglyceride transfer protein (MTTP protein, were observed in the liver although MTTP mRNA levels were higher in steers compared to bulls. In conclusion, FA synthesis may contribute to increased hepatic lipid deposition in steers following castration. However, hepatic lipid metabolism, including triglyceride synthesis, FA oxidation, and VLDL secretion, was not significantly altered by castration. Our results suggest that hepatic lipid metabolism does not significantly contribute to increased body fat deposition in steers following castration.

Evaluation of chemical castration with calcium chloride versus surgical castration in donkeys: testosterone as an endpoint marker.

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Ibrahim, Ahmed; Ali, Magda M; Abou-Khalil, Nasser S; Ali, Marwa F

2016-03-08

For the last few years, researchers have been interested in developing a method for chemical sterilization which may be a better alternative to surgical castration. An ideal chemical sterilant would be one that effectively arrests spermatogenesis and androgenesis as well as libido with absence of toxic or other side effects. Calcium chloride in various solutions and concentrations has been tested in many animal species, but few studies have been evaluated it in equines as a chemical sterilant. So, the objective of this study was to evaluate the clinical efficacy of chemical castration with 20% calcium chloride dissolved in absolute ethanol in comparison with surgical castration in donkeys based on the changes in the serum testosterone level and the histopathological changes in treated testes. Twelve clinically healthy adult male donkeys were used in this study. Donkeys were divided randomly and equally into two groups: a surgical (S) group (n = 6) and a chemical (C) group (n = 6). Animals in the (S) group were subjected to surgical castration while those in the (C) group received a single bilateral intratesticular injection of 20% calcium chloride dissolved in absolute ethanol (20 ml/testis). Animals were kept under clinical observation for 60 days. Changes in animals' behavior and gross changes in external genitalia were monitored daily. Serum concentrations of testosterone were measured prior to treatment and at 15, 30, 45 and 60 days post-treatment. Testicles in the (C) group were examined histopathologically at the end of the experiment. Chemical castration with intratesticular calcium chloride vs. surgical castration failed to reduce serum concentrations of testosterone throughout the whole duration of the study; however it induced orchitis that was evident by focal necrotic areas in seminiferous tubules, cellular infiltration of neutrophils, proliferative intertubular fibrosis with a compensatory proliferation of Leydig cells. Donkeys tolerated the

Retardation of muscle growth in castrated male mice: further ...

African Journals Online (AJOL)

Retardation of muscle growth in castrated male mice was studied as an evidence for the influence of hormones on the development of muscle mass. Male albino mice were castrated at 28days of age by open castration method. The weights and the muscle mass indices (mg muscle weight per gram body weight) of the ...

Silencing CAPN2 Expression Inhibited Castration-Resistant Prostate Cancer Cells Proliferation and Invasion via AKT/mTOR Signal Pathway

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Pu Li

2017-01-01

Full Text Available The mRNA expression of CAPN2 was upregulated in CRPC cells (DU145 and PC3 than that in non-CRPC cells. Silencing CAPN2 expression could inhibit DU145 and PC3 cells proliferation by cell cycle arrest at G1 phase. Knockdown of CPAN2 level suppressed the migration and invasion capacity of CRPC cells by reducing matrix metalloproteinase-2 (MMP-2 and MMP-9 activation, as well as repressing the phosphorylation protein expression of AKT and mTOR. In addition, we found that the expression of CAPN2 was elevated in Pca tissues than that in normal control tissues. Therefore, we showed the important roles of CAPN2 in the development and progression in CRPC cells, suggesting a new therapeutic intervention for treating castration-resistant prostate cancer patients.

Novel Junction-specific and Quantifiable In Situ Detection of AR-V7 and its Clinical Correlates in Metastatic Castration-resistant Prostate Cancer.

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Zhu, Yezi; Sharp, Adam; Anderson, Courtney M; Silberstein, John L; Taylor, Maritza; Lu, Changxue; Zhao, Pei; De Marzo, Angelo M; Antonarakis, Emmanuel S; Wang, Mindy; Wu, Xingyong; Luo, Yuling; Su, Nan; Nava Rodrigues, Daniel; Figueiredo, Ines; Welti, Jonathan; Park, Emily; Ma, Xiao-Jun; Coleman, Ilsa; Morrissey, Colm; Plymate, Stephen R; Nelson, Peter S; de Bono, Johann S; Luo, Jun

2018-05-01

Androgen receptor splice variant 7 (AR-V7) has been implicated in resistance to abiraterone and enzalutamide treatment in men with metastatic castration-resistant prostate cancer (mCRPC). Tissue- or cell-based in situ detection of AR-V7, however, has been limited by lack of specificity. To address current limitations in precision measurement of AR-V7 by developing a novel junction-specific AR-V7 RNA in situ hybridization (RISH) assay compatible with automated quantification. We designed a RISH method to visualize single splice junctions in cells and tissue. Using the validated assay for junction-specific detection of the full-length AR (AR-FL) and AR-V7, we generated quantitative data, blinded to clinical data, for 63 prostate tumor biopsies. We evaluated clinical correlates of AR-FL/AR-V7 measurements, including association with prostate-specific antigen progression-free survival (PSA-PFS) and clinical and radiographic progression-free survival (PFS), in a subset of patients starting treatment with abiraterone or enzalutamide following biopsy. Quantitative AR-FL/AR-V7 data were generated from 56 of the 63 (88.9%) biopsy specimens examined, of which 44 were mCRPC biopsies. Positive AR-V7 signals were detected in 34.1% (15/44) mCRPC specimens, all of which also co-expressed AR-FL. The median AR-V7/AR-FL ratio was 11.9% (range 2.7-30.3%). Positive detection of AR-V7 was correlated with indicators of high disease burden at baseline. Among the 25 CRPC biopsies collected before treatment with abiraterone or enzalutamide, positive AR-V7 detection, but not higher AR-FL, was significantly associated with shorter PSA-PFS (hazard ratio 2.789, 95% confidence interval 1.12-6.95; p=0.0081). We report for the first time a RISH method for highly specific and quantifiable detection of splice junctions, allowing further characterization of AR-V7 and its clinical significance. Higher AR-V7 levels detected and quantified using a novel method were associated with poorer response to

Loss of TRPV2 Homeostatic Control of Cell Proliferation Drives Tumor Progression

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Sonia Liberati

2014-02-01

Full Text Available Herein we evaluate the involvement of the TRPV2 channel, belonging to the Transient Receptor Potential Vanilloid channel family (TRPVs, in development and progression of different tumor types. In normal cells, the activation of TRPV2 channels by growth factors, hormones, and endocannabinoids induces a translocation of the receptor from the endosomal compartment to the plasma membrane, which results in abrogation of cell proliferation and induction of cell death. Consequently, loss or inactivation of TRPV2 signaling (e.g., glioblastomas, induces unchecked proliferation, resistance to apoptotic signals and increased resistance to CD95-induced apoptotic cell death. On the other hand, in prostate cancer cells, Ca2+-dependent activation of TRPV2 induced by lysophospholipids increases the invasion of tumor cells. In addition, the progression of prostate cancer to the castration-resistant phenotype is characterized by de novo TRPV2 expression, with higher TRPV2 transcript levels in patients with metastatic cancer. Finally, TRPV2 functional expression in tumor cells can also depend on the presence of alternative splice variants of TRPV2 mRNA that act as dominant-negative mutant of wild-type TRPV2 channels, by inhibiting its trafficking and translocation to the plasma membrane. In conclusion, as TRP channels are altered in human cancers, and their blockage impair tumor progression, they appear to be a very promising targets for early diagnosis and chemotherapy.

Methylated Glutathione S-transferase 1 (mGSTP1) is a potential plasma free DNA epigenetic marker of prognosis and response to chemotherapy in castrate-resistant prostate cancer

OpenAIRE

Mahon, K L; Qu, W; Devaney, J; Paul, C; Castillo, L; Wykes, R J; Chatfield, M D; Boyer, M J; Stockler, M R; Marx, G; Gurney, H; Mallesara, G; Molloy, P L; Horvath, L G; Clark, S J

2014-01-01

Background: Glutathione S-transferase 1 (GSTP1) inactivation is associated with CpG island promoter hypermethylation in the majority of prostate cancers (PCs). This study assessed whether the level of circulating methylated GSTP1 (mGSTP1) in plasma DNA is associated with chemotherapy response and overall survival (OS). Methods: Plasma samples were collected prospectively from a Phase I exploratory cohort of 75 men with castrate-resistant PC (CRPC) and a Phase II independent validation cohort ...

Custirsen in combination with docetaxel and prednisone for patients with metastatic castration-resistant prostate cancer (SYNERGY trial): a phase 3, multicentre, open-label, randomised trial.

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Chi, Kim N; Higano, Celestia S; Blumenstein, Brent; Ferrero, Jean-Marc; Reeves, James; Feyerabend, Susan; Gravis, Gwenaelle; Merseburger, Axel S; Stenzl, Arnulf; Bergman, Andries M; Mukherjee, Som D; Zalewski, Pawel; Saad, Fred; Jacobs, Cindy; Gleave, Martin; de Bono, Johann S

2017-04-01

Clusterin is a chaperone protein associated with treatment resistance and upregulated by apoptotic stressors such as chemotherapy. Custirsen is a second-generation antisense oligonucleotide that inhibits clusterin production. The aim of the SYNERGY trial was to investigate the effect of custirsen in combination with docetaxel and prednisone on overall survival in patients with metastatic castration-resistant prostate cancer. SYNERGY was a phase 3, multicentre, open-label, randomised trial set at 134 study centres in 12 countries. Patients were eligible for participation if they had: metastatic castration-resistant prostate cancer and had received no previous chemotherapy; prostate-specific antigen greater than 5 ng/mL; and a Karnofsky performance score of 70% or higher. Patients were randomly assigned 1:1 centrally to either the docetaxel, prednisone, and custirsen combination or docetaxel and prednisone alone. Patients were not masked to treatment allocation. Randomisation was stratified by opioid use for cancer-related pain and radiographic evidence of progression. All patients received docetaxel 75 mg/m 2 intravenously with 5 mg of prednisone orally twice daily. Patients assigned docetaxel, prednisone, and custirsen received weekly doses of custirsen 640 mg intravenously after three loading doses of 640 mg. The primary endpoint was overall survival analysed in the intention-to-treat population. Patients who received at least one study dose were included in the safety analysis set. This trial is registered with ClinicalTrials.gov, number NCT01188187. The trial is completed and final analyses are reported here. Between Dec 10, 2010, and Nov 7, 2012, 1022 patients were enrolled to the trial, of whom 510 were assigned docetaxel, prednisone, and custirsen and 512 were allocated docetaxel and prednisone. No difference in overall survival was recorded between the two groups (median survival 23·4 months [95% CI 20·9-24·8] with docetaxel, prednisone, and custirsen vs

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

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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.

Bladder outlet obstruction (BOO) in men with castration-resistant prostate cancer.

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Rom, Maximilian; Waldert, Matthias; Schatzl, Georg; Swietek, Natalia; Shariat, Shahrokh F; Klatte, Tobias

2014-07-01

To evaluate the frequency of bladder outlet obstruction (BOO) and detrusor overactivity (DO) in patients with castration-resistant prostate cancer (CRPC) and lower urinary tract symptoms (LUTS). Our prospective urodynamics database was queried. Inclusion criteria were CRPC and an International Prostate Symptom Score (IPSS) ≥ 20. Exclusion criteria were previous local therapy to the prostate gland, known urethral stricture disease, and a neurological component of LUTS. Twenty-one patients were identified. Urodynamic findings were analysed and compared with those of a matched cohort of 42 patients with benign prostatic enlargement (BPE). The median age of patients in the CRPC group was 74 years, and the median prostate-specific antigen (PSA) level at the time of the urodynamic study was 90 ng/mL. According to the BOO index, three patients (14%) were obstructed, three were equivocally obstructed (14%) and 15 were unobstructed. DO was seen in 12 patients (57%). Compared with the BPE group, patients with CRPC had lower cystometric bladder capacities (P = 0.003), were less likely to have BOO (14 vs 43%, P = 0.009) and more likely to have DO (57 vs 29%, P = 0.028). This study generates the hypothesis that only a minority of CRPC patients with LUTS have BOO, and that more than half of patients have DO. LUTS in CRPC may therefore be seldom attributable to BOO, but are, at least in part, related to DO and reduced cystometric capacity. A urodynamic investigation may be necessary before palliative transurethral resection of the prostate to select appropriate candidates. Larger prospective studies are needed to confirm our findings. © 2013 The Authors. BJU International © 2013 BJU International.

Melatonin Inhibits Androgen Receptor Splice Variant-7 (AR-V7)-Induced Nuclear Factor-Kappa B (NF-κB) Activation and NF-κB Activator-Induced AR-V7 Expression in Prostate Cancer Cells: Potential Implications for the Use of Melatonin in Castration-Resistant Prostate Cancer (CRPC) Therapy.

Science.gov (United States)

Liu, Vincent Wing Sun; Yau, Wing Lung; Tam, Chun Wai; Yao, Kwok-Ming; Shiu, Stephen Yuen Wing

2017-05-31

A major current challenge in the treatment of advanced prostate cancer, which can be initially controlled by medical or surgical castration, is the development of effective, safe, and affordable therapies against progression of the disease to the stage of castration resistance. Here, we showed that in LNCaP and 22Rv1 prostate cancer cells transiently overexpressing androgen receptor splice variant-7 (AR-V7), nuclear factor-kappa B (NF-κB) was activated and could result in up-regulated interleukin ( IL ) -6 gene expression, indicating a positive interaction between AR-V7 expression and activated NF-κB/IL-6 signaling in castration-resistant prostate cancer (CRPC) pathogenesis. Importantly, both AR-V7-induced NF-κB activation and IL-6 gene transcription in LNCaP and 22Rv1 cells could be inhibited by melatonin. Furthermore, stimulation of AR-V7 mRNA expression in LNCaP cells by betulinic acid, a pharmacological NF-κB activator, was reduced by melatonin treatment. Our data support the presence of bi-directional positive interactions between AR-V7 expression and NF-κB activation in CRPC pathogenesis. Of note, melatonin, by inhibiting NF-κB activation via the previously-reported MT₁ receptor-mediated antiproliferative pathway, can disrupt these bi-directional positive interactions between AR-V7 and NF-κB and thereby delay the development of castration resistance in advanced prostate cancer. Apparently, this therapeutic potential of melatonin in advanced prostate cancer/CRPC management is worth translation in the clinic via combined androgen depletion and melatonin repletion.

Melatonin Inhibits Androgen Receptor Splice Variant-7 (AR-V7-Induced Nuclear Factor-Kappa B (NF-κB Activation and NF-κB Activator-Induced AR-V7 Expression in Prostate Cancer Cells: Potential Implications for the Use of Melatonin in Castration-Resistant Prostate Cancer (CRPC Therapy

Directory of Open Access Journals (Sweden)

Vincent Wing Sun Liu

2017-05-01

Full Text Available A major current challenge in the treatment of advanced prostate cancer, which can be initially controlled by medical or surgical castration, is the development of effective, safe, and affordable therapies against progression of the disease to the stage of castration resistance. Here, we showed that in LNCaP and 22Rv1 prostate cancer cells transiently overexpressing androgen receptor splice variant-7 (AR-V7, nuclear factor-kappa B (NF-κB was activated and could result in up-regulated interleukin (IL-6 gene expression, indicating a positive interaction between AR-V7 expression and activated NF-κB/IL-6 signaling in castration-resistant prostate cancer (CRPC pathogenesis. Importantly, both AR-V7-induced NF-κB activation and IL-6 gene transcription in LNCaP and 22Rv1 cells could be inhibited by melatonin. Furthermore, stimulation of AR-V7 mRNA expression in LNCaP cells by betulinic acid, a pharmacological NF-κB activator, was reduced by melatonin treatment. Our data support the presence of bi-directional positive interactions between AR-V7 expression and NF-κB activation in CRPC pathogenesis. Of note, melatonin, by inhibiting NF-κB activation via the previously-reported MT1 receptor-mediated antiproliferative pathway, can disrupt these bi-directional positive interactions between AR-V7 and NF-κB and thereby delay the development of castration resistance in advanced prostate cancer. Apparently, this therapeutic potential of melatonin in advanced prostate cancer/CRPC management is worth translation in the clinic via combined androgen depletion and melatonin repletion.

Erlotinib is a viable treatment for tumors with acquired resistance to cetuximab

Science.gov (United States)

Brand, Toni M; Dunn, Emily F; Iida, Mari; Myers, Rebecca A; Kostopoulos, Kellie T; Li, Chunrong; Peet, Chimera R

2011-01-01

The epidermal growth factor receptor (EGFR) is an ubiquitously expressed receptor tyrosine kinase (RTK) and is recognized as a key mediator of tumorigenesis in many human tumors. Currently there are five EGFR inhibitors used in oncology, two monoclonal antibodies (panitumumab and cetuximab) and three tyrosine kinase inhibitors (erlotinib, gefitinib and lapatinib). Both strategies of EGFR inhibition have demonstrated clinical success; however, many tumors remain non-responsive or acquire resistance during therapy. To explore potential molecular mechanisms of acquired resistance to cetuximab we previously established a series of cetuximab-resistant clones by chronically exposing the NCI-H226 NSCLC cell line to escalating doses of cetuximab. Cetuximab-resistant clones exhibited a dramatic increase in the activation of EGFR, HER2 and HER3 receptors as well as increased signaling through the MAP K and AKT pathways. RNAi studies demonstrated dependence of cetuximab-resistant clones on the EGFR signaling network. These findings prompted investigation on whether or not cells with acquired resistance to cetuximab would be sensitive to the EGFR targeted TKI erlotinib. In vitro, erlotinib was able to decrease signaling through the EGFR axis, decrease cellular proliferation and induce apoptosis. To determine if erlotinib could have therapeutic benefit in vivo, we established cetuximab-resistant NCI-H226 mouse xenografts, and subsequently treated them with erlotinib. Mice harboring cetuximab-resistant tumors treated with erlotinib exhibited either a tumor regression or growth delay as compared with vehicle controls. Analysis of the erlotinib treated tumors demonstrated a decrease in cell proliferation and increased rates of apoptosis. The work presented herein suggests that (1) cells with acquired resistance to cetuximab maintain their dependence on EGFR and (2) tumors developing resistance to cetuximab can benefit from subsequent treatment with erlotinib, providing rationale

Platelet-camouflaged nanococktail: Simultaneous inhibition of drug-resistant tumor growth and metastasis via a cancer cells and tumor vasculature dual-targeting strategy.

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Jing, Lijia; Qu, Haijing; Wu, Dongqi; Zhu, Chaojian; Yang, Yongbo; Jin, Xing; Zheng, Jian; Shi, Xiangsheng; Yan, Xiufeng; Wang, Yang

2018-01-01

Multidrug resistance (MDR) poses a great challenge to cancer therapy. It is difficult to inhibit the growth of MDR cancer due to its chemoresistance. Furthermore, MDR cancers are more likely to metastasize, causing a high mortality among cancer patients. In this study, a nanomedicine RGD-NPVs@MNPs/DOX was developed by encapsulating melanin nanoparticles (MNPs) and doxorubicin (DOX) inside RGD peptide (c(RGDyC))-modified nanoscale platelet vesicles (RGD-NPVs) to efficiently inhibit the growth and metastasis of drug-resistant tumors via a cancer cells and tumor vasculature dual-targeting strategy. Methods: The in vitro immune evasion potential and the targeting performance of RGD-NPVs@MNPs/DOX were examined using RAW264.7, HUVECs, MDA-MB-231 and MDA-MB-231/ADR cells lines. We also evaluated the pharmacokinetic behavior and the in vivo therapeutic performance of RGD-NPVs@MNPs/DOX using a MDA-MB-231/ADR tumor-bearing nude mouse model. Results: By taking advantage of the self-recognizing property of the platelet membrane and the conjugated RGD peptides, RGD-NPVs@MNPs/DOX was found to evade immune clearance and target the αvβ3 integrin on tumor vasculature and resistant breast tumor cells. Under irradiation with a NIR laser, RGD-NPVs@MNPs/DOX produced a multipronged effect, including reversal of cancer MDR, efficient killing of resistant cells by chemo-photothermal therapy, elimination of tumor vasculature for blocking metastasis, and long-lasting inhibition of the expressions of VEGF, MMP2 and MMP9 within the tumor. Conclusion: This versatile nanomedicine of RGD-NPVs@MNPs/DOX integrating unique biomimetic properties, excellent targeting performance, and comprehensive therapeutic strategies in one formulation might bring opportunities to MDR cancer therapy.

Morphologic and biochemical changes in male rat lung after surgical and pharmacological castration

Directory of Open Access Journals (Sweden)

M.S. Ojeda

2000-03-01

Full Text Available The morphology of the rat lung was studied by light microscopy in different situations: after surgical and pharmacological castration and after administration of testosterone to the castrated rat to determine if the androgen is required to maintain the normal morphology of the lung. We also determined the effect of flutamide on the phospholipid composition of both the surfactant and microsomes of the lung. Rats were separated into five groups: I - control non-castrated rats, II - castrated rats sacrificed 21 days after castration, III - castrated rats that received testosterone daily from day 2 to day 21 after castration, IV - castrated rats that received testosterone from day 15 to day 21 after castration, and V - control rats injected with flutamide for 7 days. The amount of different phospholipids in the surfactant and microsomes of the lung was measured in group I and V rats. At the light microscopy level, the surgical and pharmacological castration provoked alterations in the morphology of the lung, similar to that observed in human lung emphysema. The compositions of surfactant and microsomes of the lung were similar to those previously reported by us for the surgically castrated rats. These results indicate that androgens are necessary for the normal morphology as well as for some metabolic aspects of the lung.

Progesterone receptor expression during prostate cancer progression suggests a role of this receptor in stromal cell differentiation.

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Yu, Yue; Yang, Ou; Fazli, Ladan; Rennie, Paul S; Gleave, Martin E; Dong, Xuesen

2015-07-01

The progesterone receptor, like the androgen receptor, belongs to the steroid receptor superfamily. Our previous studies have reported that the PR is expressed specifically in prostate stroma. PR inhibits proliferation of, and regulates cytokine secretion by stromal cells. However, PR protein expression in cancer-associated stroma during prostate cancer progression has not been profiled. Since the phenotypes of prostate stromal cells change dynamically as tumors progress, whether the PR plays a role in regulating stromal cell differentiation needs to be investigated. Immunohistochemistry assays measured PR protein levels on human prostate tissue microarrays containing 367 tissue cores from benign prostate, prostate tumors with different Gleason scores, tumors under various durations of castration therapy, and tumors at the castration-resistant stage. Immunoblotting assays determined whether PR regulated the expression of alpha smooth muscle actin (α-SMA), vimentin, and fibroblast specific protein (FSP) in human prostate stromal cells. PR protein levels decreased in cancer-associated stroma when compared with that in benign prostate stroma. This reduction in PR expression was not correlated with Gleason scores. PR protein levels were elevated by castration therapy, but reduced to pre-castration levels when tumors progressed to the castration-resistant stage. Enhanced PR expression in human prostate stromal cells increased α-SMA, but decreased vimentin and FSP protein levels ligand-independently. These results suggest that PR plays an active role in regulating stromal cell phenotypes during prostate cancer progression. © 2015 Wiley Periodicals, Inc.

Phase II Study of Pomalidomide in Patients with Castration-Resistant Prostate Cancer

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Amato, Robert J., E-mail: robert.amato@uth.tmc.edu [Memorial Hermann Cancer Center, University of Texas, 6410 Fannin Street, Suite 830, Houston, TX 77030 (United States); Glode, L. Michael [Health Science Center, University of Colorado, Denver, CO 80217 (United States); University of Colorado Cancer Center, Aurora, CO 80045 (United States); Podolnick, Jeremy [Memorial Hermann Cancer Center, University of Texas, 6410 Fannin Street, Suite 830, Houston, TX 77030 (United States); Knight, Robert [Celgene Corporation, Summit, NJ 07901-3915 (United States); Crawford, David [Health Science Center, University of Colorado, Denver, CO 80217 (United States); University of Colorado Cancer Center, Aurora, CO 80045 (United States)

2011-09-02

Pomalidomide is a distinct immunomodulatory agent that also displays anti-proliferative and proapoptotic activity. The purpose of this study was to assess the efficacy and safety of pomalidomide for the treatment of chemotherapy-naïve patients with metastatic castration-resistant prostate cancer (CRPC). Methods: Pomalidomide was administered orally in doses of 1 or 2 mg/day without interruption. Follow ups were conducted every 4 weeks with evaluation of study outcomes at 12 weeks. The principal study outcomes were PSA response, time to progression (TTP) using RECIST, overall survival (OS), and safety. A total of 32 patients were enrolled: 15 in the 1 mg/day cohort (median baseline PSA level of 12.30 ng/mL [0.8–236.0]), and 17 in the 2 mg/day cohort (median baseline PSA level of 12.50 ng/mL [0.6–191.8]). Results: In the 1 mg cohort disease was stabilized for ≥28 days in eight patients, and median TTP was 2.90 months. In the 2 mg cohort, PSA decreased ≥50% in three patients, disease was stabilized for ≥28 days in seven patients, and median TTP was 5.87 months. Toxicity in both cohorts was predominantly grade 1 or 2; 2 grade 3 toxicity (fatigue) occurred in the 1 mg cohort, and 5 grade 3 toxicities (chest pain, diarrhea, epigastric pain, impaction, pain) occurred in the 2 mg cohort. One grade 4 toxicity of cardiac ischemia occurred. Conclusions: Pomalidomide shows promising activity in patients with CRPC and has an acceptable safety profile.

Phase II Study of Pomalidomide in Patients with Castration-Resistant Prostate Cancer

International Nuclear Information System (INIS)

Amato, Robert J.; Glode, L. Michael; Podolnick, Jeremy; Knight, Robert; Crawford, David

2011-01-01

Pomalidomide is a distinct immunomodulatory agent that also displays anti-proliferative and proapoptotic activity. The purpose of this study was to assess the efficacy and safety of pomalidomide for the treatment of chemotherapy-naïve patients with metastatic castration-resistant prostate cancer (CRPC). Methods: Pomalidomide was administered orally in doses of 1 or 2 mg/day without interruption. Follow ups were conducted every 4 weeks with evaluation of study outcomes at 12 weeks. The principal study outcomes were PSA response, time to progression (TTP) using RECIST, overall survival (OS), and safety. A total of 32 patients were enrolled: 15 in the 1 mg/day cohort (median baseline PSA level of 12.30 ng/mL [0.8–236.0]), and 17 in the 2 mg/day cohort (median baseline PSA level of 12.50 ng/mL [0.6–191.8]). Results: In the 1 mg cohort disease was stabilized for ≥28 days in eight patients, and median TTP was 2.90 months. In the 2 mg cohort, PSA decreased ≥50% in three patients, disease was stabilized for ≥28 days in seven patients, and median TTP was 5.87 months. Toxicity in both cohorts was predominantly grade 1 or 2; 2 grade 3 toxicity (fatigue) occurred in the 1 mg cohort, and 5 grade 3 toxicities (chest pain, diarrhea, epigastric pain, impaction, pain) occurred in the 2 mg cohort. One grade 4 toxicity of cardiac ischemia occurred. Conclusions: Pomalidomide shows promising activity in patients with CRPC and has an acceptable safety profile

Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer.

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Fizazi, Karim; Tran, NamPhuong; Fein, Luis; Matsubara, Nobuaki; Rodriguez-Antolin, Alfredo; Alekseev, Boris Y; Özgüroğlu, Mustafa; Ye, Dingwei; Feyerabend, Susan; Protheroe, Andrew; De Porre, Peter; Kheoh, Thian; Park, Youn C; Todd, Mary B; Chi, Kim N

2017-07-27

Abiraterone acetate, a drug that blocks endogenous androgen synthesis, plus prednisone is indicated for metastatic castration-resistant prostate cancer. We evaluated the clinical benefit of abiraterone acetate plus prednisone with androgen-deprivation therapy in patients with newly diagnosed, metastatic, castration-sensitive prostate cancer. In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 1199 patients to receive either androgen-deprivation therapy plus abiraterone acetate (1000 mg daily, given once daily as four 250-mg tablets) plus prednisone (5 mg daily) (the abiraterone group) or androgen-deprivation therapy plus dual placebos (the placebo group). The two primary end points were overall survival and radiographic progression-free survival. After a median follow-up of 30.4 months at a planned interim analysis (after 406 patients had died), the median overall survival was significantly longer in the abiraterone group than in the placebo group (not reached vs. 34.7 months) (hazard ratio for death, 0.62; 95% confidence interval [CI], 0.51 to 0.76; P<0.001). The median length of radiographic progression-free survival was 33.0 months in the abiraterone group and 14.8 months in the placebo group (hazard ratio for disease progression or death, 0.47; 95% CI, 0.39 to 0.55; P<0.001). Significantly better outcomes in all secondary end points were observed in the abiraterone group, including the time until pain progression, next subsequent therapy for prostate cancer, initiation of chemotherapy, and prostate-specific antigen progression (P<0.001 for all comparisons), along with next symptomatic skeletal events (P=0.009). These findings led to the unanimous recommendation by the independent data and safety monitoring committee that the trial be unblinded and crossover be allowed for patients in the placebo group to receive abiraterone. Rates of grade 3 hypertension and hypokalemia were higher in the abiraterone group. The addition of abiraterone

Surgical castration, coercion and ethics

DEFF Research Database (Denmark)

Ryberg, Jesper; Petersen, Thomas Søbirk

2014-01-01

the only means by which these offenders are likely to be released from prison, it is reasonable—and close to the heart of modern medical ethics—to consider whether the offer involves some kind of coercion. However, despite McMillan's seemingly careful consideration of this question, it appears to us......John McMillan's detailed ethical analysis concerning the use of surgical castration of sex offenders in the Czech Republic and Germany is mainly devoted to considerations of coercion.1 This is not surprising. When castration is offered as an option to offenders and, at the same time, constitutes...

LSD1 activates a lethal prostate cancer gene network independently of its demethylase function.

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Sehrawat, Archana; Gao, Lina; Wang, Yuliang; Bankhead, Armand; McWeeney, Shannon K; King, Carly J; Schwartzman, Jacob; Urrutia, Joshua; Bisson, William H; Coleman, Daniel J; Joshi, Sunil K; Kim, Dae-Hwan; Sampson, David A; Weinmann, Sheila; Kallakury, Bhaskar V S; Berry, Deborah L; Haque, Reina; Van Den Eeden, Stephen K; Sharma, Sunil; Bearss, Jared; Beer, Tomasz M; Thomas, George V; Heiser, Laura M; Alumkal, Joshi J

2018-05-01

Medical castration that interferes with androgen receptor (AR) function is the principal treatment for advanced prostate cancer. However, clinical progression is universal, and tumors with AR-independent resistance mechanisms appear to be increasing in frequency. Consequently, there is an urgent need to develop new treatments targeting molecular pathways enriched in lethal prostate cancer. Lysine-specific demethylase 1 (LSD1) is a histone demethylase and an important regulator of gene expression. Here, we show that LSD1 promotes the survival of prostate cancer cells, including those that are castration-resistant, independently of its demethylase function and of the AR. Importantly, this effect is explained in part by activation of a lethal prostate cancer gene network in collaboration with LSD1's binding protein, ZNF217. Finally, that a small-molecule LSD1 inhibitor-SP-2509-blocks important demethylase-independent functions and suppresses castration-resistant prostate cancer cell viability demonstrates the potential of LSD1 inhibition in this disease.

Targeting the interleukin-11 receptor α in metastatic prostate cancer: A first-in-man study.

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Pasqualini, Renata; Millikan, Randall E; Christianson, Dawn R; Cardó-Vila, Marina; Driessen, Wouter H P; Giordano, Ricardo J; Hajitou, Amin; Hoang, Anh G; Wen, Sijin; Barnhart, Kirstin F; Baze, Wallace B; Marcott, Valerie D; Hawke, David H; Do, Kim-Anh; Navone, Nora M; Efstathiou, Eleni; Troncoso, Patricia; Lobb, Roy R; Logothetis, Christopher J; Arap, Wadih

2015-07-15

Receptors in tumor blood vessels are attractive targets for ligand-directed drug discovery and development. The authors have worked systematically to map human endothelial receptors ("vascular zip codes") within tumors through direct peptide library selection in cancer patients. Previously, they selected a ligand-binding motif to the interleukin-11 receptor alpha (IL-11Rα) in the human vasculature. The authors generated a ligand-directed, peptidomimetic drug (bone metastasis-targeting peptidomimetic-11 [BMTP-11]) for IL-11Rα-based human tumor vascular targeting. Preclinical studies (efficacy/toxicity) included evaluating BMTP-11 in prostate cancer xenograft models, drug localization, targeted apoptotic effects, pharmacokinetic/pharmacodynamic analyses, and dose-range determination, including formal (good laboratory practice) toxicity across rodent and nonhuman primate species. The initial BMTP-11 clinical development also is reported based on a single-institution, open-label, first-in-class, first-in-man trial (National Clinical Trials number NCT00872157) in patients with metastatic, castrate-resistant prostate cancer. BMTP-11 was preclinically promising and, thus, was chosen for clinical development in patients. Limited numbers of patients who had castrate-resistant prostate cancer with osteoblastic bone metastases were enrolled into a phase 0 trial with biology-driven endpoints. The authors demonstrated biopsy-verified localization of BMTP-11 to tumors in the bone marrow and drug-induced apoptosis in all patients. Moreover, the maximum tolerated dose was identified on a weekly schedule (20-30 mg/m(2) ). Finally, a renal dose-limiting toxicity was determined, namely, dose-dependent, reversible nephrotoxicity with proteinuria and casts involving increased serum creatinine. These biologic endpoints establish BMTP-11 as a targeted drug candidate in metastatic, castrate-resistant prostate cancer. Within a larger discovery context, the current findings indicate that

The Androgen-Regulated Calcium-Activated Nucleotidase 1 (CANT1) Is Commonly Overexpressed in Prostate Cancer and Is Tumor-Biologically Relevant in Vitro

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Gerhardt, Josefine; Steinbrech, Corinna; Büchi, Oralea; Behnke, Silvia; Bohnert, Annette; Fritzsche, Florian; Liewen, Heike; Stenner, Frank; Wild, Peter; Hermanns, Thomas; Müntener, Michael; Dietel, Manfred; Jung, Klaus; Stephan, Carsten; Kristiansen, Glen

2011-01-01

Previously, we identified the calcium-activated nucleotidase 1 (CANT1) transcript as up-regulated in prostate cancer. Now, we studied CANT1 protein expression in a large cohort of nearly 1000 prostatic tissue samples including normal tissue, prostatic intraepithelial neoplasia (PIN), primary carcinomas, metastases, and castrate-resistant carcinomas, and further investigated its functional relevance. CANT1 displayed predominantly a Golgi-type immunoreactivity with additional and variable cytoplasmic staining. In comparison to normal tissues, the staining intensity was significantly increased in PIN lesions and cancer. In cancer, high CANT1 levels were associated with a better prognosis, and castrate-resistant carcinomas commonly showed lower CANT1 levels than primary carcinomas. The functional role of CANT1 was investigated using RNA interference in two prostate cancer cell lines with abundant endogenous CANT1 protein. On CANT1 knockdown, a significantly diminished cell number and DNA synthesis rate, a cell cycle arrest in G1 phase, and a strong decrease of cell transmigration rate and wound healing capacity of CANT1 knockdown cells was found. However, on forced CANT1 overexpression, cell proliferation and migration remained unchanged. In summary, CANT1 is commonly overexpressed in the vast majority of primary prostate carcinomas and in the precursor lesion PIN and may represent a novel prognostic biomarker. Moreover, this is the first study to demonstrate a functional involvement of CANT1 in tumor biology. PMID:21435463

Second-Line Hormonal Therapy for Men With Chemotherapy-Naïve, Castration-Resistant Prostate Cancer: American Society of Clinical Oncology Provisional Clinical Opinion.

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Virgo, Katherine S; Basch, Ethan; Loblaw, D Andrew; Oliver, Thomas K; Rumble, R Bryan; Carducci, Michael A; Nordquist, Luke; Taplin, Mary-Ellen; Winquist, Eric; Singer, Eric A

2017-06-10

Purpose ASCO provisional clinical opinions (PCOs) offer direction to the ASCO membership after publication or presentation of potential practice-changing data. This PCO addresses second-line hormonal therapy for chemotherapy-naïve men with castration-resistant prostate cancer (CRPC) who range from being asymptomatic with only biochemical evidence of CRPC to having documented metastases but minimal symptoms. Clinical Context The treatment goal for CRPC is palliation. Despite resistance to initial androgen deprivation therapy, most men respond to second-line hormonal therapies. However, guidelines have neither addressed second-line hormonal therapy for nonmetastatic CRPC nor provided specific guidance with regard to the chemotherapy-naïve population. Recent Data Six phase III randomized controlled trials and expert consensus opinion inform this PCO. Provisional Clinical Opinion For men with CRPC, a castrate state should be maintained indefinitely. Second-line hormonal therapy (eg, antiandrogens, CYP17 inhibitors) may be considered in patients with nonmetastatic CRPC at high risk for metastatic disease (rapid prostate-specific antigen doubling time or velocity) but otherwise is not suggested. In patients with radiographic evidence of metastases and minimal symptoms, enzalutamide or abiraterone plus prednisone should be offered after discussion with patients about potential harms, benefits, costs, and patient preferences. Radium-223 and sipuleucel-T also are options. No evidence provides guidance about the optimal order of hormonal therapies for CRPC beyond second-line treatment. Prostate-specific antigen testing every 4 to 6 months is reasonable for men without metastases. Routine radiographic restaging generally is not suggested but can be considered for patients at risk for metastases or who exhibit symptoms or other evidence of progression. Additional information is available at www.asco.org/genitourinary-cancer-guidelines and www.asco.org/guidelineswiki .

Alterations in tumor necrosis factor signaling pathways are associated with cytotoxicity and resistance to taxanes: a study in isogenic resistant tumor cells

Science.gov (United States)

2012-01-01

Introduction The taxanes paclitaxel and docetaxel are widely used in the treatment of breast, ovarian, and other cancers. Although their cytotoxicity has been attributed to cell-cycle arrest through stabilization of microtubules, the mechanisms by which tumor cells die remains unclear. Paclitaxel has been shown to induce soluble tumor necrosis factor alpha (sTNF-α) production in macrophages, but the involvement of TNF production in taxane cytotoxicity or resistance in tumor cells has not been established. Our study aimed to correlate alterations in the TNF pathway with taxane cytotoxicity and the acquisition of taxane resistance. Methods MCF-7 cells or isogenic drug-resistant variants (developed by selection for surviving cells in increasing concentrations of paclitaxel or docetaxel) were assessed for sTNF-α production in the absence or presence of taxanes by enzyme-linked immunosorbent assay (ELISA) and for sensitivity to docetaxel or sTNF-α by using a clonogenic assay (in the absence or presence of TNFR1 or TNFR2 neutralizing antibodies). Nuclear factor (NF)-κB activity was also measured with ELISA, whereas gene-expression changes associated with docetaxel resistance in MCF-7 and A2780 cells were determined with microarray analysis and quantitative reverse transcription polymerase chain reaction (RTqPCR). Results MCF-7 and A2780 cells increased production of sTNF-α in the presence of taxanes, whereas docetaxel-resistant variants of MCF-7 produced high levels of sTNF-α, although only within a particular drug-concentration threshold (between 3 and 45 nM). Increased production of sTNF-α was NF-κB dependent and correlated with decreased sensitivity to sTNF-α, decreased levels of TNFR1, and increased survival through TNFR2 and NF-κB activation. The NF-κB inhibitor SN-50 reestablished sensitivity to docetaxel in docetaxel-resistant MCF-7 cells. Gene-expression analysis of wild-type and docetaxel-resistant MCF-7, MDA-MB-231, and A2780 cells identified changes

Lu-177-PSMA-617 Prostate-Specific Membrane Antigen Inhibitor Therapy in Patients with Castration-Resistant Prostate Cancer: Stability, Bio-distribution and Dosimetry

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Levent Kabasakal

2017-06-01

Full Text Available Objective: The aim of the study was to estimate the radiation-absorbed doses and to study the in vivo and in vitro stability as well as pharmacokinetic characteristics of lutetium-177 (Lu-177 prostate-specific membrane antigen (PSMA-617. Methods: For this purpose, 7 patients who underwent Lu-177-PSMA therapy were included into the study. The injected Lu-177-PSMA-617 activity ranged from 3.6 to 7.4 GBq with a mean of 5.2±1.8 GBq. The stability of radiotracer in saline was calculated up to 48 h. The stability was also calculated in blood and urine samples. Post-therapeutic dosimetry was performed based on whole body and single photon emission computed tomography/computed tomography (SPECT/CT scans on dual-headed SPECT/CT system. Results: The radiochemical yield of Lu-177-PSMA-617 was >99%. It remained stable in saline up to 48 h. Analyses of the blood and urine samples showed a single radioactivity peak even at 24 hours after injection. Half-life of the distribution and elimination phases were calculated to be 0.16±0.09 and 10.8±2.5 hours, respectively. The mean excretion rate was 56.5±8.8% ranging from 41.5% to 65.4% at 24 h. Highest radiation estimated doses were calculated for parotid glands and kidneys (1.90±1.19 and 0.82±0.25 Gy/GBq respectively. Radiation dose given to the bone marrow was significantly lower than those of kidney and parotid glands (p<0.05 (0.030±0.008 Gy/GBq. Conclusion: Lu-177-PSMA-617 is a highly stable compound both in vitro and in vivo. Lu-177-PSMA-617 therapy seems to be a safe method for the treatment of castration-resistant prostate cancer patients. The fractionation regime that enables the longest duration of tumor control and/or survival will have to be developed in further studies.

Effect of timing of subcutaneous meloxicam administration on indicators of pain after knife castration of weaned calves.

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Meléndez, D M; Marti, S; Pajor, E A; Moya, D; Gellatly, D; Janzen, E D; Schwartzkopf-Genswein, K S

2017-12-01

The newly revised Canadian Codes of Practice for the management of beef cattle requires that as of 2018, calves older than 6 mo of age be castrated using pain control. Castration is a husbandry procedure commonly done without pain control, and there is a lack of agreement on an effective pain mitigation strategy specific to castration. The aim of this study was to identify the optimal time of administration of meloxicam prior to castration. Thirty-four Angus and Angus crossbred bull calves (282 ± 28.0 kg BW) were randomly assigned to 1 of 3 treatments receiving a single s.c. injection of meloxicam (0.5 mg/kg BW): 6 h (6H; = 11), 3 h (3H; = 12), or immediately (0H; = 11) before knife castration. Measurements included visual analog scale (VAS), head movement (HM), accelerometer movement (AM) and strain gauge exertion force (EF) on the squeeze chute, stride length (SL), lying and standing behavior, salivary cortisol (SC), haptoglobin, serum amyloid A (SAA), substance P (SP), and scrotal temperature (ST). Samples were collected on d -7, -5, -2, -1, and immediately before castration (T0) and 30, 60, 120, and 240 min and 1, 2, 5, 7, 14, 21, and 28 d after castration, except for VAS, AM, EF, and HM, which were obtained at the time of castration. A time × treatment effect ( = 0.01) was observed for SP, where 0H had lower concentrations than 3H and 6H calves 1 d after castration, whereas 3H calves tended to have greater levels than 6H calves 5 d after castration. Mean ST was greater ( castration, whereas 6H and 3H calves had greater ST compared to 0H calves 240 min after castration. On d 1 after castration, 6H calves had greater ST than 0H and 3H calves, whereas 0H calves had greater ST compared to 3H and 6H calves on d 28 after castration. The SL tended ( = 0.09) to be shorter in 3H and 6H calves than 0H calves 30, 60, 120, and 240 min after castration. Number of peaks from the AM between 2 and 3 SD above or below the mean were greater ( = 0.03) in 3H and 6H calves than

Castration, dopamine and food choice: a cost/benefit test in male hamsters.

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Chu, Lucy; Wood, Ruth I

2002-10-17

Testosterone is essential for copulation, and contributes to sexual motivation. In addition, castrated males are fatter and less active, suggesting that androgens may play a role in non-sexual behaviors, including food-related responses. To test this hypothesis, male hamsters were trained with a cost/benefit test, which compares operant responding for more-preferred food versus ad libitum consumption of lab chow. Males were tested before and after castration. The effect of the dopamine antagonist, haloperidol, on instrumental responses in intact and castrated males was also determined. Food-deprived hamsters responded vigorously for 45 mg Bio-Serv pellets in daily 30-min tests (665 presses, 6.0+/-0.9 g). When lab chow was available, males continued to respond for pellets (3.6+/-0.6 g) over chow ad libitum (1.2+/-0.3 g). Dopamine is central to this response because haloperidol (1.0 mg/kg i.p.) reversed food intake (pellets: 0.5+/-0.1 g; chow 2.0+/-0.5 g). Castration had no effect on operant responding for pellets alone (6.6+/-0.7 g). When chow was present, castrates consumed an even greater proportion of their total food intake as pellets [6.0+/-0.4 g pellets (92%), 1.6+/-0.5 g chow (8%), vs. 75 and 25%, respectively, for intact males]. This is contrary to our original hypothesis. In addition, castration did not change the effects of haloperidol on food intake: (0.4+/-0.1 g pellets; 1.6+/-0.5 g chow). These results support previous findings in rats that dopamine affects response allocation in a cost/benefit test. However, they do not support the hypothesis that testosterone modifies the allocation of food-related responses.

Current perspectives on the optimal age to spay/castrate dogs and cats

Directory of Open Access Journals (Sweden)

Howe LM

2015-05-01

Full Text Available Lisa M HoweDepartment of Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USAAbstract: Spaying and castrating of dogs and cats has been considered for decades to be a routine standard of practice in veterinary medicine in the US for the prevention of numerous undesirable behaviors, medical conditions, and diseases. Additionally, the procedures have been promoted as a method of curbing the severe pet-overpopulation problem in the US. Recently, however, this routine practice has come under scrutiny and become a very controversial topic. The general wisdom and safety of the procedures have been questioned by those who are concerned that the procedures may have some unintended consequences that are only recently being recognized. The purpose of this paper is to critically examine the scientific literature regarding elective spay/castration procedures and present both risks and benefits of elective gonadectomy. After the literature is examined, it becomes clear that there may not be a single absolute optimal age to spay or castrate all dogs and cats, but that the optimal age may be dependent upon several factors, including species, breed, body size, and breed-specific diseases, among others. Determining the optimal age to perform elective gonadectomy is much clearer in cats, and the literature demonstrates that the procedures can typically be safely performed at any age after 6–8 weeks of age. The optimal age to spay or castrate dogs of certain breeds (rottweiler, golden retriever, Labrador retriever, and vizsla is becoming less clear as studies are being conducted as to the health benefits and risks in those breeds. This review will examine these controversies and make recommendations as to the optimal age to spay/castrate dogs based upon the scientific literature.Keywords: gonadectomy (neuter, ovariohysterectomy (spay, castration, neoplasia, longevity, orthopedic

Healing of surgical castration wounds: a description and an evaluation of flunixin.

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Mintline, E M; Varga, A; Banuelos, J; Walker, K A; Hoar, B; Drake, Daniel; Weary, D M; Coetzee, J F; Stock, M L; Tucker, C B

2014-12-01

Previous studies have shown that surgical castration wounds take between 10 and 61 d to heal. The objectives of this work were to describe healing, inflammation, lying behavior, and serum concentration of substance P after surgical castration in beef calves and to evaluate the effect of a possible intervention, a single injection of flunixin meglumine (1.1 mg/kg IV, a NSAID), on the healing process. Calves (mean±SE: 25±2.0 d of age; 54±1.4 kg BW) were surgically castrated with or without an injection of flunixin immediately before the procedure (n=24/treatment). Healing was measured with a 5-point scale (1=fresh wound, 5=no visible incision or inflammation) as well as weight gain, scrotal size, and scrotal surface temperature, on d 1, 2, 3, 7, 14, 21, 28, 35, 49, and 63 after castration. Serum concentration of substance P was recorded on all d, including d 0, but not d 63. Lying behavior was recorded with loggers from 2 d before to 29 d after castration. Inflammation, as measured by scrotal size, peaked on d 2 and 3 after the procedure (e.g., 51±1.0 mm on d 2 versus 28±1.3 mm before castration) and then declined with time (Pcastration (41±1.2 pg/mL), possibly because the sample was collected after the lidocaine ring block was administered, which was likely painful, and because of separation from the dam and restraint. Values began to drop by d 3 (34±1.2 pg/mL) and leveled out by d 21 (30±1.2 pg/mL; Pcastration caused inflammation in the days that followed, and the wounds required a minimum of 4 wk to heal. Provision of an NSAID had no effect on these outcomes.

Approaches to drug resistance in solid tumors : with emphasis on lung cancer

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Bakker, Marleen

2005-01-01

De novo or acquired resistance of tumor cells to anticancer agents remains a major problem for the therapeutic efficacy of chemotherapeutic drugs. Most solid tumors are intrinsically insensitive or acquire resistance after initial response to chemotherapy. Different mechanisms seem to play a role in

A survey of castration methods and associated livestock management practices performed by bovine veterinarians in the United States.

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Coetzee, Johann F; Nutsch, Abbey L; Barbur, Laura A; Bradburn, Ryan M

2010-03-03

Castration of male calves destined for beef production is a common management practice performed in the United States amounting to approximately 15 million procedures per year. Societal concern about the moral and ethical treatment of animals is increasing. Therefore, production agriculture is faced with the challenge of formulating animal welfare policies relating to routine management practices such as castration. To enable the livestock industry to effectively respond to these challenges there is a need for more data on management practices that are commonly used in cattle production systems. The objective of this survey was to describe castration methods, adverse events and husbandry procedures performed by U.S. veterinarians at the time of castration. Invitations to participate in the survey were sent to email addresses of 1,669 members of the American Association of Bovine Practitioners and 303 members of the Academy of Veterinary Consultants. After partially completed surveys and missing data were omitted, 189 responses were included in the analysis. Surgical castration with a scalpel followed by testicular removal by twisting (calves 90 kg) was the most common method of castration used. The potential risk of injury to the operator, size of the calf, handling facilities and experience with the technique were the most important considerations used to determine the method of castration used. Swelling, stiffness and increased lying time were the most prevalent adverse events observed following castration. One in five practitioners report using an analgesic or local anesthetic at the time of castration. Approximately 90% of respondents indicated that they vaccinate and dehorn calves at the time of castration. Over half the respondents use disinfectants, prophylactic antimicrobials and tetanus toxoid to reduce complications following castration. The results of this survey describe current methods of castration and associated management practices employed by

A survey of castration methods and associated livestock management practices performed by bovine veterinarians in the United States

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Bradburn Ryan M

2010-03-01

Full Text Available Abstract Background Castration of male calves destined for beef production is a common management practice performed in the United States amounting to approximately 15 million procedures per year. Societal concern about the moral and ethical treatment of animals is increasing. Therefore, production agriculture is faced with the challenge of formulating animal welfare policies relating to routine management practices such as castration. To enable the livestock industry to effectively respond to these challenges there is a need for more data on management practices that are commonly used in cattle production systems. The objective of this survey was to describe castration methods, adverse events and husbandry procedures performed by U.S. veterinarians at the time of castration. Invitations to participate in the survey were sent to email addresses of 1,669 members of the American Association of Bovine Practitioners and 303 members of the Academy of Veterinary Consultants. Results After partially completed surveys and missing data were omitted, 189 responses were included in the analysis. Surgical castration with a scalpel followed by testicular removal by twisting (calves 90 kg was the most common method of castration used. The potential risk of injury to the operator, size of the calf, handling facilities and experience with the technique were the most important considerations used to determine the method of castration used. Swelling, stiffness and increased lying time were the most prevalent adverse events observed following castration. One in five practitioners report using an analgesic or local anesthetic at the time of castration. Approximately 90% of respondents indicated that they vaccinate and dehorn calves at the time of castration. Over half the respondents use disinfectants, prophylactic antimicrobials and tetanus toxoid to reduce complications following castration. Conclusions The results of this survey describe current methods of

Effect of castration on performance and profitability of finishing cattle in rent feedlot

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Marcos Aurélio Lopes

2011-01-01

Full Text Available Effects of castration on performance and profitability of finishing beef cattle in feedlot was evaluated and compared to no-castrated animals. Data came from a rent feedlot of beef cattle, conducted from August to November of 2005. Half of 50 animals, randomly chosen, were castrated by knife 18 days before the beginning of feedlot. Averages of initial body weight for castrated and no-castrated animals were 341kg and 347kg, while for final body weight were 437kg and 463kg, respectively. Were considered as expenses arroba value of thin cattle (R$50.00, and R$2.85 daily expenses per animal paid by cattle owner to “boitel”; and were considered as earnings sale of fat cattle at R$56.14 and R$54.14/arroba, respectively for castrated and no-castrated animals. For profitability analysis, CU$TO BOVINO CORTE software was utilized. Was tested the mean differences between castrated and intact groups by Student t test of average daily weight gains (GMPD and total weight gain (GMPT. Was acceptable the minimum level of confidence of 95%. Statistical analysis was performed in SPSS 17.0 program. Effect of castration negatively influenced animals´ performance, evaluated by weight gain, and, consequently profitability of the system, evaluated by net margin. Earnings from sale of additional arrobas of no-castrated animals were enough to compensate penalization practiced by packinghouses for these animals.

Tyrosine isomers mediate the classical phenomenon of concomitant tumor resistance.

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Ruggiero, Raúl A; Bruzzo, Juan; Chiarella, Paula; di Gianni, Pedro; Isturiz, Martín A; Linskens, Susana; Speziale, Norma; Meiss, Roberto P; Bustuoabad, Oscar D; Pasqualini, Christiane D

2011-11-15

Concomitant tumor resistance (CR) is a phenomenon originally described in 1906 in which a tumor-bearing host is resistant to the growth of secondary tumor implants and metastasis. Although recent studies have indicated that T-cell-dependent processes mediate CR in hosts bearing immunogenic small tumors, manifestations of CR induced by immunogenic and nonimmunogenic large tumors have been associated with an elusive serum factor. In this study, we identify this serum factor as tyrosine in its meta and ortho isoforms. In three different murine models of cancer that generate CR, both meta-tyrosine and ortho-tyrosine inhibited tumor growth. In addition, we showed that both isoforms of tyrosine blocked metastasis in a fourth model that does not generate CR but is sensitive to CR induced by other tumors. Mechanistic studies showed that the antitumor effects of the tyrosine isoforms were mediated, in part, by early inhibition of mitogen-activated protein/extracellular signal-regulated kinase pathway and inactivation of STAT3, potentially driving tumor cells into a state of dormancy. By revealing a molecular basis for the classical phenomenon of CR, our findings may stimulate new generalized approaches to limit the development of metastases that arise after resection of primary tumors, an issue of pivotal importance to oncologists and their patients. ©2011 AACR

Pain in castration-resistant prostate cancer with bone metastases: a qualitative study

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Gater Adam

2011-10-01

Full Text Available Abstract Background Bone metastases are a common painful and debilitating consequence of castration-resistant prostate cancer (CPRC. Bone pain may predict patients' prognosis and there is a need to further explore CRPC patients' experiences of bone pain in the overall context of disease pathology. Due to the subjective nature of pain, assessments of pain severity, onset and progression are reliant on patient assessment. Patient reported outcome (PRO measures, therefore, are commonly used as key endpoints for evaluating the efficacy of CRPC treatments. Evidence of the content validity of leading PRO measures of pain severity used in CRPC clinical trials is, however, limited. Methods To document patients' experience of CRPC symptoms including pain, and their impact on health-related quality of life (HRQL, semi-structured in-depth qualitative interviews were conducted with 17 patients with CRPC and bone metastases. The content validity of the Present Pain Intensity (PPI scale from the McGill Pain Questionnaire (MPQ, and the 'Average Pain' and 'Worst Pain' items of the Brief Pain Inventory Short-Form (BPI-SF was also assessed. Results Patients with CRPC and bone metastases present with a constellation of symptoms that can have a profound effect on HRQL. For patients in this study, bone pain was the most prominent and debilitating symptom associated with their condition. Bone pain was chronic and, despite being generally well-managed by analgesic medication, instances of breakthrough cancer pain (BTcP were common. Cognitive debriefing of the selected PRO measures of pain severity highlighted difficulties among patients in understanding the verbal response scale (VRS of the MPQ PPI scale. There were also some inconsistencies in the way in which the BPI-SF 'Average Pain' item was interpreted by patients. In contrast, the BPI-SF 'Worst Pain' item was well understood and interpreted consistently among patients. Conclusions Study findings support the

Chemical Quality of Male Etawah Crossbred and Castrated Boer Crossbred Goat Meat

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Djalal Rosyidi

2012-02-01

Full Text Available The aim of this study was to know the chemical quality (moisture, protein, fat, calcium, phosphorus of male Etawah crossbred and castrated Boer crossbred goat meat. The result expected can be used as further information about the chemical quality of male Etawah crossbred and castrated Boer crossbred goat meat and as future researches. The material of the research were loin meat, front and back thigh of male Etawah crossbred and castrated Boer crossbred goat, these meat parts were the fineground and 10 gram were taken for sample preparation. The result show that the different species of goat statistically was no significant effect (P>0.05 on moisture, protein, fat, calcium and  phosphorus. The chemical quality of male Etawah crossbred and castrated Boer crossbred goat (moisture obtained from vacuum oven, fat from soxhlet, protein from semimicro kejldahl, calcium and phosphorus from Spectrophotometer is (71.080%, 69.886%; 17.120%, 17.907%; 8.358%, 8.981%; 13.846 mg/100g, 18.811mg/100g; 134.817mg/100g, 151.032mg/100g. The conclusion was moisture content from male Etawah crossbred was higher than castrated Boer crossbred, but fat, protein, calcium, and phosphorus content castrated Boer crossbred were higher than castrated Boer crossbred.   Keywords: male Etawah crossbred, castrated Boer crossbred, moisture

Temporal patterns of inflammatory gene expression in local tissues after banding or burdizzo castration in cattle.

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Pang, Wanyong; Earley, Bernadette; Sweeney, Torres; Gath, Vivian; Crowe, Mark A

2009-09-23

Castration of male cattle has been shown to elicit inflammatory reactions and acute inflammation is initiated and sustained by the participation of cytokines. Sixty continental x beef bulls (Mean age 12 +/- (s.e.) 0.2 months; Mean weight 341 +/- (s.e.) 3.0 kg) were blocked by weight and randomly assigned to one of three treatments (n = 20 animals per treatment): 1) untreated control (Con); 2) banding castration at 0 min (Band); 3) Burdizzo castration at 0 min (Burd). Samples of the testis, epididymis and scrotal skin were collected surgically from 5 animals from each group at 12 h, 24 h, 7 d, and 14 d post-treatment, and analysed using real-time PCR. A repeated measurement analysis (Proc GLM) was performed using SAS. If there was no treatment and time interaction, main effects of treatment by time were tested by ANOVA. Electrophoresis data showed that by 7 d post-castration RNA isolated from all the testicle samples of the Burd castrated animals, the epididymis and middle scrotum samples from Band castrates were degraded. Transitory effects were observed in the gene expression of IFN-gamma, IL-6, IL-8 and TNF-alpha at 12 h and 24 h post treatment. Burd castrates had greater (P castrates had greater (P castrates at 12 h post-castration. Burd castrates had greater (P castration. In the epididymis, Burd castrates had greater (P castrates had greater (P = 0.049) IL-10 mRNA levels than Band castrates at 12 h post-castration. Banding castration caused more inflammatory associated gene expression changes to the epididymis and scrotum than burdizzo. Burdizzo caused more severe acute inflammatory responses, in terms of pro-inflammatory cytokine gene expression, in the testis and epididymis than banding.

Factors determining sensitivity or resistance of tumor cell lines towards artesunate.

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Sertel, Serkan; Eichhorn, Tolga; Sieber, Sebastian; Sauer, Alexandra; Weiss, Johanna; Plinkert, Peter K; Efferth, Thomas

2010-04-15

Clinical oncology is still challenged by the development of drug resistance of tumors that result in poor prognosis for patients. There is an urgent necessity to understand the molecular mechanisms of resistance and to develop novel therapy strategies. Artesunate (ART) is an anti-malarial drug, which also exerts profound cytotoxic activity towards cancer cells. We first applied a gene-hunting approach using cluster and COMPARE analyses of microarray-based transcriptome-wide mRNA expression profiles. Among the genes identified by this approach were genes from diverse functional groups such as structural constituents of ribosomes (RPL6, RPL7, RPS12, RPS15A), kinases (CABC1, CCT2, RPL41), transcriptional and translational regulators (SFRS2, TUFM, ZBTB4), signal transducers (FLNA), control of cell growth and proliferation (RPS6), angiogenesis promoting factors (ITGB1), and others (SLC25A19, NCKAP1, BST1, DBH, FZD7, NACA, MTHFD2). Furthermore, we applied a candidate gene approach and tested the role of resistance mechanisms towards established anti-cancer drugs for ART resistance. By using transfected or knockout cell models we found that the tumor suppressor p16(INK4A) and the anti-oxidant protein, catalase, conferred resistance towards ART, while the oncogene HPV-E6 conferred sensitivity towards ART. The tumor suppressor p53 and its downstream protein, p21, as well as the anti-oxidant manganese-dependent superoxide dismutase did not affect cellular response to ART. In conclusion, our pharmacogenomic approach revealed that response of tumor cells towards ART is multi-factorial and is determined by gene expression associated with either ART sensitivity or resistance. At least some of the functional groups of genes (e.g. angiogenesis promoting factors, cell growth and proliferation-associated genes signal transducers and kinases) are also implicated in clinical responsiveness of tumors towards chemotherapy. It merits further investigation, whether ART is responsive in

Major vault protein/lung resistance-related protein (MVP/LRP) expression in nervous system tumors.

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Sasaki, Tsutomu; Hankins, Gerald R; Helm, Gregory A

2002-01-01

Lung resistance-related protein (LRP) was identified as the major vault protein (MVP), the main component of multimeric vault particles. It functions as a transport-associated protein that can be associated with multidrug resistance. In previous studies, expression of MVP/LRP has been documented in tumors of various types. In general, good correlations have been reported for expression of MVP/LRP and decreased sensitivity to chemotherapy and poor prognosis. MVP/LRP expression has been documented in glioblastomas, but its expression in nervous system tumors in general has not been well characterized. Immunohistochemistry using anti-human MVP/LRP antibody (LRP-56) was performed on formalin-fixed, paraffin-embedded archival tissue from 69 primary central nervous system tumors. Expression of MVP/LRP was observed in 81.2% (56/69) of primary nervous system tumors, including astrocytomas (11/13), oligodendrogliomas (1/2), oligoastrocytomas (5/5), ependymoma (1/1), meningiomas (35/45), schwannomas (2/2), and neurofibroma (1/1). Various degrees and distributions of immunoreactivity to MVP/ LRP were observed. Neither the presence nor the degree of immunoreactivity to MVP/LRP showed any correlation with either tumor grade or the presence of brain invasion.

Sensitivity to ionizing radiation and chemotherapeutic agents in gemcitabine-resistant human tumor cell lines

NARCIS (Netherlands)

van Bree, Chris; Castro Kreder, Natasja; Loves, Willem J. P.; Franken, Nicolaas A. P.; Peters, Godefridus J.; Haveman, Jaap

2002-01-01

Purpose: To determine cross-resistance to anti-tumor treatments in 2',2'difluorodeoxycytidine (dFdC, gemcitabine)-resistant human tumor cells. Methods and Materials: Human lung carcinoma cells SW-1573 (SWp) were made resistant to dFdC (SWg). Sensitivity to cisplatin (cDDP), paclitaxel,

Epidemiology of surgical castration of dogs and cats in the United States.

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Trevejo, Rosalie; Yang, Mingyin; Lund, Elizabeth M

2011-04-01

To estimate the prevalence of surgical castration among dogs and cats evaluated at private US veterinary hospitals and to determine the influence of sex, age, breed, geographic location, and prepaid wellness plan enrollment on the likelihood of castration. Retrospective period prevalence study. 320,172 cats and 1,339,860 dogs examined at 651 hospitals during 2007 Procedures-Univariate and multivariate analyses were used to compare prevalence among subpopulations for each species. The overall prevalence of castration was 82% in cats and 64% in dogs. Prevalence increased significantly with age in both species. Among cats, males were slightly more likely to be castrated than females (prevalence ratio [PR] = 1.03) and mixed breeds slightly less likely than purebreds (PR = 0.99). Among dogs, males were less likely to be castrated than females (PR = 0.93) and mixed breeds more likely than purebreds (PR = 1.19). Prevalence was lowest in dogs in the Southeastern United States (61%). Dogs and cats on a wellness plan were more likely to be castrated than those not on a plan (PR = 1.33 and 1.18, respectively). Among commonly reported dog breeds, pit bull-type dogs (27%) and Chihuahuas (46%) were least likely to be castrated. Many young adult (1- to Chihuahua), and dogs in the Southeastern United States. Additional research is needed to evaluate the potential impact of wellness programs on an owner's decision to have his or her pet castrated.

Hepatic transcriptional changes in critical genes for gluconeogenesis following castration of bulls

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Fassah, Dilla Mareistia; Jeong, Jin Young

2018-01-01

Objective This study was performed to understand transcriptional changes in the genes involved in gluconeogenesis and glycolysis pathways following castration of bulls. Methods Twenty Korean bulls were weaned at average 3 months of age, and castrated at 6 months. Liver tissues were collected from bulls (n = 10) and steers (n = 10) of Korean cattle, and hepatic gene expression levels were measured using quantitative real-time polymerase chain reaction. We examined hepatic transcription levels of genes encoding enzymes for irreversible reactions in both gluconeogenesis and glycolysis as well as genes encoding enzymes for the utilization of several glucogenic substrates. Correlations between hepatic gene expression and carcass characteristics were performed to understand their associations. Results Castration increased the mRNA (3.6 fold; pgluconeogenesis reactions from pyruvate to glucose and enzymes responsible for incorporation of glucogenic substrates including lactate, glycerol, and propionate. Hepatic gluconeogenic gene expression levels were associated with intramuscular fat deposition. PMID:29502393

Effects of a topical anaesthetic formulation and systemic carprofen, given singly or in combination, on the cortisol and behavioural responses of Merino lambs to castration.

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Paull, D R; Lee, C; Colditz, I G; Fisher, A D

2009-06-01

To determine the effectiveness of a topical anaesthetic formulation (Tri-Solfen) with or without the administration of a non-steroidal anti-inflammatory drug (carprofen) on the pain and distress response associated with ring or surgical castration of ram lambs. Merino ram lambs (n = 78) were allocated to 10 treatment groups: 4 groups of knife-castrated lambs and 4 groups of ring-castrated lambs received carprofen (4 mg/kg SC) and Tri-Solfen; 2 control groups (sham) received carprofen at 0 or 4 mg/kg SC. Measurements included plasma cortisol and haptoglobin concentrations, haematology, and behaviour, including posture. Knife-castrated lambs had higher peak cortisol and integrated cortisol responses for the first 6 h after treatment and greater concentration s of circulating acute phase proteins than ring-castrated lambs, both of which were significantly different from the sham controls. Tri-Solfen applied to the knife castration wound significantly reduced both the peak plasma cortisol concentration and the integrated cortisol response for the first 6 h and improved lying behaviour in the first 12 h. Carprofen reduced the cortisol response to knife castration at 30 min, but elevated the cortisol responses at 24 and 48 h. Carprofen nearly halved the number of acute pain behaviours associated with ring castration. There were no significant additive or synergistic effects from combining the analgesic treatments. Tri-Solfen applied to the tail wound provided no detectible benefits during ring castration + tail docking. The physiological and behavioural responses suggest that ring castration has less impact on the lamb than knife castration. The specific analgesic treatments can provide modest amelioration of the pain and discomfort associated with castration. Alternative doses or application methods may enhance their efficacy.

Prostate radiation in non-metastatic castrate refractory prostate cancer provides an interesting insight into biology of prostate cancer

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Pascoe Abigail C

2012-03-01

Full Text Available Abstract Background The natural history of non-metastatic castrate refractory prostate cancer is unknown and treatment options are limited. We present a retrospective review of 13 patients with locally advanced or high risk prostate cancer, initially treated with hormone monotherapy and then treated with prostate radiation after becoming castration refractory. Findings Median PSA response following prostate radiation was 67.4%. Median time to biochemical progression following radiotherapy was 15 months and to detection of metastatic disease was 18.5 months. Median survival from castration resistance (to date of death or November 2011 was 60 months, with median survival from RT 42 months. Conclusion Prostate radiation appears to be beneficial even in patients with potential micrometastatic disease, which supports the hypothesis that the primary tumour is important in the progression of prostate cancer. These results are an interesting addition to the literature on the biology of prostate cancer especially as this data is unlikely to be available in the future due to combined prostate radiation and androgen deprivation therapy now being the standard of care.

A meta-analysis of cortisol concentration, vocalization, and average daily gain associated with castration in beef cattle.

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Canozzi, Maria Eugênia Andrighetto; Mederos, America; Manteca, Xavier; Turner, Simon; McManus, Concepta; Zago, Daniele; Barcellos, Júlio Otávio Jardim

2017-10-01

A systematic review and meta-analysis (MA) were performed to summarize all scientific evidence for the effects of castration in male beef cattle on welfare indicators based on cortisol concentration, average daily gain (ADG), and vocalization. We searched five electronic databases, conference proceedings, and experts were contacted electronically. The main inclusion criteria involved completed studies using beef cattle up to one year of age undergoing surgical and non-surgical castration that presented cortisol concentration, ADG, or vocalization as an outcome. A random effect MA was conducted for each indicator separately with the mean of the control and treated groups. A total of 20 publications reporting 26 studies and 162 trials were included in the MA involving 1814 cattle. Between study heterogeneity was observed when analysing cortisol (I 2 =56.7%) and ADG (I 2 =79.6%). Surgical and non-surgical castration without drug administration compared to uncastrated animals showed no change (P≥0.05) in cortisol level. Multimodal therapy for pain did not decrease (P≥0.05) cortisol concentration after 30min when non-surgical castration was performed. Comparison between surgical castration, with and without anaesthesia, showed a tendency (P=0.077) to decrease cortisol levels after 120min of intervention. Non-surgical and surgical castration, performed with no pain mitigation, increased and tended to increase the ADG by 0.814g/d (P=0.001) and by 0.140g/d (P=0.091), respectively, when compared to a non-castrated group. Our MA study demonstrates an inconclusive result to draw recommendations on preferred castration practices to minimize pain in beef cattle. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effect of local infusion of NSAID analgesics administered alone or in combination on the pain associated with band castration in calves.

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Paull, D R; Small, A H; Lee, C; Labeur, L; Colditz, I G

2015-08-01

To evaluate the analgesic efficacy of flunixin alone or in combination with diclofenac administered locally to the scrotum at the time of band castration of calves. Angus bull calves (n = 40; ≈7-9 weeks old) were allocated to four treatment groups (n = 10 per group) to examine the effects of two non-steroidal anti-inflammatory analgesics (NSAIDs) administered locally at the time of band castration: sham control; castration + flunixin; castration + flunixin + diclofenac; castration + saline. The NSAIDs and saline were administered subcutaneously into the scrotum under the band. Blood was sampled at -0.5, 0.5, 1.5, 3, 12, 24, 48 and 72 h relative to castration. Haematology parameters and plasma cortisol levels were determined in samples at all time points and plasma haptoglobin levels determined in samples collected at -0.5, 24, 48 and 72 h. Pain avoidance and postural behaviours were measured for 2 and 12 h, respectively, after castration. Band-castrated calves exhibited significantly higher peak cortisol and higher integrated cortisol responses during the first 6 h post-castration relative to sham controls. Individual active pain avoidance behaviours observed for 1 h post-castration were not significantly different between treatment groups; however; the sum of the total behaviours was significantly increased by castration (P = 0.023). Postural changes included increased abnormal ventral lying for all castrated groups and decreased normal standing and increased combined abnormal postures for the flunixin- and saline-treated groups. Growth rates of calves were not affected by treatments during weeks 1 and 2 post-castration; however, growth rates of castrated calves were significantly lower than those of sham-treated calves in week 3 post-castration (1.41 vs 0.84, 0.75 and 0.56±0.19 kg/day for sham, flunixin-, flunixin + diclofenac- and saline-treated groups, respectively). The administration of flunixin or flunixin + diclofenac intrascrotally at several sites

Budget Impact of Enzalutamide for Chemotherapy-Naïve Metastatic Castration-Resistant Prostate Cancer.

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Bui, Cat N; O'Day, Ken; Flanders, Scott; Oestreicher, Nina; Francis, Peter; Posta, Linda; Popelar, Breanna; Tang, Hong; Balk, Mark

2016-02-01

Prostate cancer is expected to account for approximately one quarter of all new diagnoses of cancer in American men in 2015. The cost of prostate cancer care is expected to reach $15.1 billion by the year 2020, up from $11.9 billion in 2010. Given the high burden of prostate cancer, health care payers are interested in quantifying the potential budget impact of new therapies. To estimate the budget impact of enzalutamide for the treatment of chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) from a U.S. payer perspective. A model was developed to assess the budget impact of enzalutamide for treatment of chemotherapy-naïve mCRPC patients in a hypothetical 1-million-member U.S. health plan over a 1-year time horizon. Comparators included abiraterone acetate, sipuleucel-T, radium Ra 223 dichloride, and docetaxel. Epidemiologic data, including National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) incidence rates, were used to estimate the number of chemotherapy-naïve mCRPC patients. Dosing, administration, duration of therapy, and adverse event rates were based on package inserts and pivotal studies. Drug costs were obtained from RED BOOK and Centers for Medicare & Medicaid Services (CMS) average sales price pricing files, costs of administration and monitoring from the CMS physician fee schedule, and adverse events from the Agency for Healthcare Research and Quality Healthcare Cost and Utilization Project and published literature. Market shares were estimated for each comparator before and after adoption of enzalutamide. The incremental aggregate budget impact, per patient per year (PPPY), per patient per month (PPPM), and per member per month (PMPM), was calculated. One-way sensitivity analyses were performed. In a population of 115 chemotherapy-naïve mCRPC patients, adopting enzalutamide had an annual incremental budget impact of $510,641 ($4,426 PPPY, $369 PPPM, and $0.04 PMPM). Results were most sensitive to

Leveraging Hypoxia-Activated Prodrugs to Prevent Drug Resistance in Solid Tumors.

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Danika Lindsay

2016-08-01

Full Text Available Experimental studies have shown that one key factor in driving the emergence of drug resistance in solid tumors is tumor hypoxia, which leads to the formation of localized environmental niches where drug-resistant cell populations can evolve and survive. Hypoxia-activated prodrugs (HAPs are compounds designed to penetrate to hypoxic regions of a tumor and release cytotoxic or cytostatic agents; several of these HAPs are currently in clinical trial. However, preliminary results have not shown a survival benefit in several of these trials. We hypothesize that the efficacy of treatments involving these prodrugs depends heavily on identifying the correct treatment schedule, and that mathematical modeling can be used to help design potential therapeutic strategies combining HAPs with standard therapies to achieve long-term tumor control or eradication. We develop this framework in the specific context of EGFR-driven non-small cell lung cancer, which is commonly treated with the tyrosine kinase inhibitor erlotinib. We develop a stochastic mathematical model, parametrized using clinical and experimental data, to explore a spectrum of treatment regimens combining a HAP, evofosfamide, with erlotinib. We design combination toxicity constraint models and optimize treatment strategies over the space of tolerated schedules to identify specific combination schedules that lead to optimal tumor control. We find that (i combining these therapies delays resistance longer than any monotherapy schedule with either evofosfamide or erlotinib alone, (ii sequentially alternating single doses of each drug leads to minimal tumor burden and maximal reduction in probability of developing resistance, and (iii strategies minimizing the length of time after an evofosfamide dose and before erlotinib confer further benefits in reduction of tumor burden. These results provide insights into how hypoxia-activated prodrugs may be used to enhance therapeutic effectiveness in the

Analysis of the Ki-67 index in the vaginal epithelium of castrated rats treated with tamoxifen

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Afif Rieth Nery-Aguiar

2016-02-01

Full Text Available OBJECTIVES: Vaginal atrophy and breast cancer are common conditions in postmenopausal women and tamoxifen is the standard endocrine treatment for hormone-sensitive tumors. The present study aimed to assess the effect of tamoxifen on Ki-67 protein expression in the vaginal epithelium of castrated rats. MATERIAL AND METHODS: Forty Wistar-Hannover adult, virgin, castrated rats were randomly divided into two groups, group I (control, n=20 and group II (tamoxifen, n=20, receiving 0.5 ml of propylene glycol and 250 µg of tamoxifen diluted in 0.5 ml of propylene glycol, respectively, daily by gavage for 30 days. On the 31st day, the rats were euthanized and their vaginas were removed and fixed in 10% buffered formalin for the immunohistochemical study of Ki-67 protein expression. Data were analyzed by the Levene and Student’s t tests (p<0.05. RESULTS: The mean index of Ki-67 expression in the rat vagina of groups I and II was 4.04±0.96 and 26.86±2.19, respectively (p<0.001. CONCLUSIONS: According to the results of the present study, tamoxifen, at the dose and treatment length used, induced a significant increase in the cell proliferation of the vaginal mucosa in castrated rats, as evaluated by Ki-67 protein expression.

Long-term weight gain and economic impact in pigs castrated under local anaesthesia

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F.G. Telles

2016-12-01

Full Text Available Castration is a controversial practice in swine production because in some countries is still performed without anaesthesia, and therefore causes intense suffering and stress to animals. This study investigated the effect of pre-surgical administration of local anaesthesia (LA on the growth performance of piglets until the end of the growth phase (102 days. Piglets aged 3 to 5 days were selected in pairs of similar weights and same age. They were originated from 22 litters. The groups were randomly assigned to one of two treatments. Castration was performed with (LA; n = 45 or without (NLA; n = 45 intra-testicular administration of 0.5 mL of 2% lidocaine plus adrenaline per testicle, administered by an automatic repeating vaccinator. Castration was performed 10 min later. Average daily weight gain and economic impact were evaluated between the intervals before castration until 21 (weaning phase, before castration until 60 (end of the initial nursery phase and before castration until 102 (growth phase days of age. Average daily weight gain data were analyzed by comparing the average daily weight gain between the weaning phase, 60 and 102 days of age versus the initial weight (pre-castration. At the end of the growing phase, animals treated with LA showed greater weight gain than animals castrated without anaesthesia. LA also showed improved cost:benefit ratio and theore might provide greater economic benefit under the conditions used in this study. Our findings have proved that castration with LA improves long-term weight gain of piglets.

Peripubertal castration of male rats, adult open field ambulation and partner preference behavior.

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Brand, T; Slob, A K

1988-09-15

The validity of the hypothesis put forward earlier, that testicular secretions during puberty have an organizing effect on open field ambulation was examined. Male rats were castrated or sham-operated at days 21, 43 or 70. At the age of 17 weeks the males were tested in an automated, octagonal open field (3 consecutive days, 3 min/day) for locomotor activity. Male rats castrated at day 21 or day 43 ambulated more than sham-castrated controls. Males castrated at day 70 did not differ from sham-castrated controls. It thus appears that pubertal testicular secretion(s) organize adult open field locomotor activity in male rats. From 18 weeks of age partner preference behavior was tested in the same open field apparatus with one adjacent cage containing an ovariectomized female and an opposite one containing an ovariectomized female brought into heat. The females in the adjacent cages were separated from the experimental males in the octagonal cage by wire mesh. Peripubertally castrated males did not show a clear-cut partner preference, whereas the intact males preferred the vicinity of the estrous female. There were no differences among the males castrated either before, during or after puberty. Testosterone treatment (crystalline T in silastic capsules) caused peripubertally castrated males to prefer the estrous female. Thus, adult partner preference behavior does not seem to be organized by peripubertal testicular androgens.

Precision medicine for advanced prostate cancer.

Science.gov (United States)

Mullane, Stephanie A; Van Allen, Eliezer M

2016-05-01

Precision cancer medicine, the use of genomic profiling of patient tumors at the point-of-care to inform treatment decisions, is rapidly changing treatment strategies across cancer types. Precision medicine for advanced prostate cancer may identify new treatment strategies and change clinical practice. In this review, we discuss the potential and challenges of precision medicine in advanced prostate cancer. Although primary prostate cancers do not harbor highly recurrent targetable genomic alterations, recent reports on the genomics of metastatic castration-resistant prostate cancer has shown multiple targetable alterations in castration-resistant prostate cancer metastatic biopsies. Therapeutic implications include targeting prevalent DNA repair pathway alterations with PARP-1 inhibition in genomically defined subsets of patients, among other genomically stratified targets. In addition, multiple recent efforts have demonstrated the promise of liquid tumor profiling (e.g., profiling circulating tumor cells or cell-free tumor DNA) and highlighted the necessary steps to scale these approaches in prostate cancer. Although still in the initial phase of precision medicine for prostate cancer, there is extraordinary potential for clinical impact. Efforts to overcome current scientific and clinical barriers will enable widespread use of precision medicine approaches for advanced prostate cancer patients.

The surgery of peripheral nerves (including tumors)

DEFF Research Database (Denmark)

Fugleholm, Kåre

2013-01-01

Surgical pathology of the peripheral nervous system includes traumatic injury, entrapment syndromes, and tumors. The recent significant advances in the understanding of the pathophysiology and cellular biology of peripheral nerve degeneration and regeneration has yet to be translated into improved...... surgical techniques and better outcome after peripheral nerve injury. Decision making in peripheral nerve surgery continues to be a complex challenge, where the mechanism of injury, repeated clinical evaluation, neuroradiological and neurophysiological examination, and detailed knowledge of the peripheral...... nervous system response to injury are prerequisite to obtain the best possible outcome. Surgery continues to be the primary treatment modality for peripheral nerve tumors and advances in adjuvant oncological treatment has improved outcome after malignant peripheral nerve tumors. The present chapter...

Effects of Topical Anaesthetic and Buccal Meloxicam Treatments on Concurrent Castration and Dehorning of Beef Calves.

Science.gov (United States)

Van der Saag, Dominique; White, Peter; Ingram, Lachlan; Manning, Jaime; Windsor, Peter; Thomson, Peter; Lomax, Sabrina

2018-02-28

The use of pain relief during castration and dehorning of calves on commercial beef operations can be limited by constraints associated with the delivery of analgesic agents. As topical anaesthetic (TA) and buccal meloxicam (MEL) are now available in Australia, offering practical analgesic treatments for concurrent castration and dehorning of beef calves, a study was conducted to determine their efficacy in providing pain relief when applied separately or in combination. Weaner calves were randomly allocated to; (1) no castration and dehorning/positive control (CONP); (2) castration and dehorning/negative control (CONN); (3) castration and dehorning with buccal meloxicam (BM); (4) castration and dehorning with topical anaesthetic (TA); and (5) castration and dehorning with buccal meloxicam and topical anaesthetic (BMTA). Weight gain, paddock utilisation, lying activity and individual behaviours following treatment were measured. CONP and BMTA calves had significantly greater weight gain than CONN calves ( p castrated calves spent more time walking ( p = 0.024) and less time eating ( p castration and amputation dehorning.

Practices and Concerns of Castration of Dogs in Nigeria | Ajadi ...

African Journals Online (AJOL)

This study evaluated the practices and concerns regarding castration, and level of awareness of Nigerian Veterinarians on alternatives to surgical castration in dogs. Questionnaires were distributed to one hundred veterinarians during the 2012 annual Veterinary Association Conference. The questionnaire comprised of the ...

Effects of pain mitigation and method of castration on behavior and feedlot performance in cull beef bulls.

Science.gov (United States)

Repenning, P E; Ahola, J K; Callan, R J; Fox, J T; French, J T; Giles, R L; Peel, R K; Whittier, J C; Engle, T E

2013-10-01

The objectives of this study were to evaluate the effects of castration method (banding vs. surgical) and use of analgesia on behavior and feedlot performance in cull bulls. Angus, Hereford, and Angus-crossbred bulls (n = 20; initial BW = 384 ± 59.3 kg; 336 ± 20.1 d old) were housed in feedlot pens equipped with the ability to measure individual daily feed intake. A balanced randomized block design using a 2 × 2 factorial arrangement of treatments was used. A multimodal analgesia (MMA) protocol was used and consisted of sutcutaneous ketamine stun containing butorphanol (0.01 mg/kg BW), xylazine (0.02 mg/kg BW), ketamine (0.04 mg/kg BW), and a local 2% lidocaine hydrochloride anesthetic block of the spermatic cords (10 mL/cord) and scrotum (10 mL) on d 0. Flunixin meglumine (1.2 mg/kg) was administered intravenously on d 0, 1, 2, and 3 to MMA cattle. Cattle were stratified to treatments based on breed, BW, age, and a temperament score. Treatments included 1) band castration without analgesia (BND), 2) band castration with analgesia (BND-MMA), 3) surgical castration without analgesia (SURG), and 4) surgical castration with analgesia (SURG-MMA). All castrations were performed on d 0. Chute exit velocity (EV) and time in chute (TIC) were collected on d -9, 0, 1, 2, and 13. Willingness-to-enter-chute (WTE) score, rectal temperature (TEMP), heart rate (HR), and respiration (RESP) were collected on d 0, 1, 2, 3, and 13. Cattle were weighed on d -9 and 13 while feeding behaviors were collected continuously for 57 d precastration and 28 d postcastration. There was a tendency (P cattle receiving analgesia. Both SURG treatments exhibited elevated TEMP on d 1 (P castrates during the first week postcastration. Results suggest that pain mitigation reduces the impact of castration on ADG and DMI.

Endoscopic Management of Vascular Sinonasal Tumors, Including Angiofibroma.

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Snyderman, Carl H; Pant, Harshita

2016-06-01

The greatest challenge in the surgical treatment of angiofibromas is dealing with the hypervascularity of these tumors. Staging systems that take into account the vascularity of the tumor may be more prognostic. A variety of treatment strategies are used to deal with the vascularity of angiofibromas, including preoperative embolization, segmentation of the tumor into vascular territories, use of hemostatic tools, and staging of surgery. Even large angiofibromas with intracranial extension and residual vascularity can be successfully managed by a skull base team using endoscopic techniques. Copyright © 2016 Elsevier Inc. All rights reserved.

Quality Characteristics and Composition of the Muscle from Entire and Castrate Elk in Korea

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Sang-Woo Kim

2016-05-01

Full Text Available The objective of the research was to determine the chemical composition as well as the physicochemical properties of the longissimus muscle from Korean entire and castrate elk. Twelve elk stags were raised and fed on concentrate with ad libitum hay. All animals were equally divided into castrated and non-castrated (entire males, and slaughtered at 5 year of age. It was found that entire elk, in comparison with castrate elk, had higher content of moisture and lower content of fat (p<0.05. Compared with entire males, the castrates had lower pH and shear force values (p<0.05. However, castrates had higher L*, a*, and b* values compared with entires (p<0.05. An analysis of the fatty acid profile revealed that the muscles of entire and castrate elk had the most abundant concentrations of the following fatty acids: palmitic acid (C16:0 of the saturated fatty acid, and oleic acid (C18:1n-9 of the unsaturated fatty acid. The entire elk contains higher proportions of linoleic acid (C18:3n6, eicosenoic acid (C20:1n9, and arachidonic acid (C20:4n6 (p<0.05. Cholesterol content in elk was not affected by castration. The predominant free amino acid was glutamic acid related to umami taste. It is apparent that the castrate animals carried higher content of histidine, isoleucine, and leucine than those of the entire group (p<0.05. In this study, it was concluded that venison quality of elk is affected by castration and these results can provide fundamental information for venison production.

Transcriptome changes favoring intramuscular fat deposition in the longissimus muscle following castration of bulls.

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Jeong, J; Bong, J; Kim, G D; Joo, S T; Lee, H-J; Baik, M

2013-10-01

Castration increases intramuscular fat (IMF) deposition, improving beef quality in cattle. The present study was performed to determine the global transcriptome changes following castration of bulls and to identify genes associated with IMF deposition in the longissimus dorsi (LM) of Korean cattle. A customized bovine CombiMatrix oligonucleotide microarray was constructed, and transcriptome changes following castration were determined by microarray hybridization. Transcriptome comparison between bulls and steers indicated that 428 of 8,407 genes were differentially expressed in the LM by greater than two fold (P castration. Castration upregulated transcription of adipogenic perilipin 2 (PLIN2) and visfatin, lipogenic fatty acid synthase, fatty acid esterification 1-acylglycerol-3-phosphate O-acyltransferase 5, and many fatty acid oxidation-related genes. Many TCA cycle and OP genes were also transcriptionally upregulated. Correlation analysis indicated that the IMF content in the LM was highly correlated with mRNA levels of PLIN2 (r = 0.70, P castration shifts transcription of lipid metabolism genes, favoring IMF deposition by increasing adipogenesis, lipogenesis, and triglyceride synthesis. This study also indicated that castration increases transcription of genes involved in fatty acid oxidation and subsequent energy production (TCA and OP genes). Our microarray analysis provided novel information that castration alters the transcriptome associated with lipid/energy metabolism, favoring IMF deposition in the LM.

Combined cytotoxic effects of tumor necrosis factor-alpha with various cytotoxic agents in tumor cell lines that are drug resistant due to mutated p53

NARCIS (Netherlands)

Sleijfer, S; Le, T. K. P.; de Jong, S.; Timmer-Bosscha, H; Withoff, S; Mulder, NH

Several studies suggest that tumor necrosis factor-alpha (TNF) is able to overcome drug resistance in tumors. Whether TNF is able to do so in tumor cell lines that are drug resistant due to a mutation in the tumor suppressor gene p53 is unclear. Therefore, we studied the in vitro cytotoxic effects

Epigenetic Modifications and Head and Neck Cancer: Implications for Tumor Progression and Resistance to Therapy

Directory of Open Access Journals (Sweden)

Rogerio M. Castilho

2017-07-01

Full Text Available Head and neck squamous carcinoma (HNSCC is the sixth most prevalent cancer and one of the most aggressive malignancies worldwide. Despite continuous efforts to identify molecular markers for early detection, and to develop efficient treatments, the overall survival and prognosis of HNSCC patients remain poor. Accumulated scientific evidences suggest that epigenetic alterations, including DNA methylation, histone covalent modifications, chromatin remodeling and non-coding RNAs, are frequently involved in oral carcinogenesis, tumor progression, and resistance to therapy. Epigenetic alterations occur in an unsystematic manner or as part of the aberrant transcriptional machinery, which promotes selective advantage to the tumor cells. Epigenetic modifications also contribute to cellular plasticity during tumor progression and to the formation of cancer stem cells (CSCs, a small subset of tumor cells with self-renewal ability. CSCs are involved in the development of intrinsic or acquired therapy resistance, and tumor recurrences or relapse. Therefore, the understanding and characterization of epigenetic modifications associated with head and neck carcinogenesis, and the prospective identification of epigenetic markers associated with CSCs, hold the promise for novel therapeutic strategies to fight tumors. In this review, we focus on the current knowledge on epigenetic modifications observed in HNSCC and emerging Epi-drugs capable of sensitizing HNSCC to therapy.

Phase I dose-escalation and pharmacokinetic study (TED 11576) of cabazitaxel in Japanese patients with castration-resistant prostate cancer.

Science.gov (United States)

Mukai, Hirofumi; Takahashi, Shunji; Nozawa, Masahiro; Onozawa, Yusuke; Miyazaki, Jun; Ohno, Keiji; Suzuki, Kazuhiro

2014-04-01

The purpose of the study is to analyze the pharmacokinetic (PK) profile of cabazitaxel and evaluate its safety and tolerability as a 1-h IV infusion every 3 weeks in Japanese patients with castration-resistant prostate cancer (CRPC). Seventeen patients were treated with cabazitaxel at doses of 20 and 25 mg/m(2) for PK analyses. Dose escalation was performed only in the absence of dose-limiting toxicity (DLT). The maximum tolerated dose (MTD) was the highest dose at which less than 33 % of the patients developed DLT. Cabazitaxel exhibited a triphasic elimination profile with a long terminal half-life of 116 ± 29.0 or 113 ± 28.0 h after IV infusion of 20 or 25 mg/m(2) cabazitaxel, respectively. The major differences in the PK parameters of cabazitaxel and docetaxel were cabazitaxel's fairly high clearance rate, representing approximately half the hepatic flow, and its large volume of distribution at steady-state conditions. No DLT was observed during Cycle 1. Mild-to-moderate hematological adverse events (AEs), including neutropenia, and other AEs typically associated with taxanes were observed; all AEs were manageable. Cabazitaxel at 25 mg/m(2) every 3 weeks was selected as the MTD in Japanese patients. The PK parameters of cabazitaxel in Japanese CRPC patients were comparable with those previously determined in Caucasian subjects. The safety and tolerability of cabazitaxel were also comparable in both ethnic populations.

Cell kinetics of Ehrlich ascites carcinoma transplanted in mice with different degrees of tumor resistance

International Nuclear Information System (INIS)

Brandt, K.L.B.

1974-01-01

Cell proliferation kinetics of Ehrlich ascites carcinoma grown in two strains of mice with different degrees of resistance to this tumor were examined. In the first portion of the study, growth of Ehrlich ascites carcinoma in nonresistant Swiss (Iowa) and slightly resistant CF1 mice was examined by measuring animal weight gain and host survival time after intraperitoneal injection of tumor cells. Since it appeared that CF1 mice were inherently more resistant than Swiss mice to the Ehrlich carcinoma, the second part of this investigation involved attempts to immunize CF1 mice against the tumor. Subcutaneous injections of Ehrlich cells previously exposed in vitro to 5000 R of 250 kVp x rays were utilized. One immunizing inoculation of lethally irradiated tumor cells afforded protection against an intraperitoneal challenge of 40 thousand Ehrlich cells. By varying the number and timing of immunizing inoculations it was possible to induce different degrees of tumor resistance in these mice. The most effective immunizing procedure utilized multiple inoculations of lethally irradiated tumor cells (LITC), followed by challenges with viable tumor cells (less than 1 million) which were rejected. These mice could then resist challenge inocula of 4 million viable tumor cells. In a few animals the immunizing procedures were ineffective; these animals, when challenged, developed even larger tumors than control mice. Tumor cell proliferation kinetics in these animals as well as in mice that were rejecting the tumor were examined in the third phase of the project. A shortening of the cell cycle was observed in almost all LITC-treated mice, whether tumor growth was eventually inhibited or stimulated. Decreased duration of the DNA-synthesis phase (S) of the tumor cell cycle was also a consistent finding. The role of the immune response in stimulating mitosis as well as in killing foreign cells was discussed. (U.S.)

ONC201 Targets AR and AR-V7 Signaling, Reduces PSA, and Synergizes with Everolimus in Prostate Cancer.

Science.gov (United States)

Lev, Avital; Lulla, Amriti R; Ross, Brian C; Ralff, Marie D; Makhov, Petr B; Dicker, David T; El-Deiry, Wafik S

2018-05-01

Androgen receptor (AR) signaling plays a key role in prostate cancer progression, and androgen deprivation therapy (ADT) is a mainstay clinical treatment regimen for patients with advanced disease. Unfortunately, most prostate cancers eventually become androgen-independent and resistant to ADT with patients progressing to metastatic castration-resistant prostate cancer (mCRPC). Constitutively activated AR variants (AR-V) have emerged as mediators of resistance to AR-targeted therapy and the progression of mCRPC, and they represent an important therapeutic target. Out of at least 15 AR-Vs described thus far, AR-V7 is the most abundant, and its expression correlates with ADT resistance. ONC201/TIC10 is the founding member of the imipridone class of small molecules and has shown anticancer activity in a broad range of tumor types. ONC201 is currently being tested in phase I/II clinical trials for advanced solid tumors, including mCRPC, and hematologic malignancies. There has been promising activity observed in patients in early clinical testing. This study demonstrates preclinical single-agent efficacy of ONC201 using in vitro and in vivo models of prostate cancer. ONC201 has potent antiproliferative and proapoptotic effects in both castration-resistant and -sensitive prostate cancer cells. Furthermore, the data demonstrate that ONC201 downregulates the expression of key drivers of prostate cancer such as AR-V7 and downstream target genes including the clinically used biomarker PSA (KLK3). Finally, the data also provide a preclinical rationale for combination of ONC201 with approved therapeutics for prostate cancer such as enzalutamide, everolimus (mTOR inhibitor), or docetaxel. Implications: The preclinical efficacy of ONC201 as a single agent or in combination, in hormone-sensitive or castration-resistant prostate cancer, suggests the potential for immediate clinical translation. Mol Cancer Res; 16(5); 754-66. ©2018 AACR . ©2018 American Association for Cancer

Baseline prostate-specific antigen levels following treatment with abiraterone acetate as a prognostic factor in castration-resistant prostate cancer.

Science.gov (United States)

Hiroshige, Tasuku; Eguchi, Yoshiro; Yoshizumi, Osamu; Chikui, Katsuaki; Kumagai, Hisaji; Kawaguchi, Yoshihiro; Onishi, Rei; Hayashi, Tokumasa; Watanabe, Kouta; Mitani, Tomotaro; Saito, Koujiro; Igawa, Tsukasa

2018-05-01

The aim of the present study was to investigate the prognostic factors associated with progression-free survival (PFS) and overall survival (OS) times in patients with castration-resistant prostate cancer (CRPC) who received treatment with abiraterone acetate (AA) in routine clinical settings. A total of 93 patients treated with AA between September 2014 and February 2017 were selected and their medical records were analyzed retrospectively. The median PFS time of docetaxel (DTX)-naïve patients was 171 days, and that of post-DTX patients was 56 days. The OS time of DTX-naïve patients did not reach the median. The median OS time of post-DTX patients was 761 days. Multivariate analyses identified baseline prostate-specific antigen (PSA) level prior to treatment with AA and the PSA response rate as independent prognostic factors for PFS time, and baseline PSA prior to treatment with AA as the only independent prognostic factor for OS time. The results of the present study indicate that the baseline PSA level prior to treatment with AA is a notable prognostic factor in patients with CRPC.

Cisplatin as an Anti-Tumor Drug: Cellular Mechanisms of Activity, Drug Resistance and Induced Side Effects

International Nuclear Information System (INIS)

Florea, Ana-Maria; Büsselberg, Dietrich

2011-01-01

Platinum complexes are clinically used as adjuvant therapy of cancers aiming to induce tumor cell death. Depending on cell type and concentration, cisplatin induces cytotoxicity, e.g., by interference with transcription and/or DNA replication mechanisms. Additionally, cisplatin damages tumors via induction of apoptosis, mediated by the activation of various signal transduction pathways, including calcium signaling, death receptor signaling, and the activation of mitochondrial pathways. Unfortunately, neither cytotoxicity nor apoptosis are exclusively induced in cancer cells, thus, cisplatin might also lead to diverse side-effects such as neuro- and/or renal-toxicity or bone marrow-suppression. Moreover, the binding of cisplatin to proteins and enzymes may modulate its biochemical mechanism of action. While a combination-chemotherapy with cisplatin is a cornerstone for the treatment of multiple cancers, the challenge is that cancer cells could become cisplatin-resistant. Numerous mechanisms of cisplatin resistance were described including changes in cellular uptake, drug efflux, increased detoxification, inhibition of apoptosis and increased DNA repair. To minimize cisplatin resistance, combinatorial therapies were developed and have proven more effective to defeat cancers. Thus, understanding of the biochemical mechanisms triggered by cisplatin in tumor cells may lead to the design of more efficient platinum derivates (or other drugs) and might provide new therapeutic strategies and reduce side effects

Cisplatin as an Anti-Tumor Drug: Cellular Mechanisms of Activity, Drug Resistance and Induced Side Effects

Energy Technology Data Exchange (ETDEWEB)

Florea, Ana-Maria [Department of Neuropathology, Heinrich-Heine University, Düsseldorf (Germany); Büsselberg, Dietrich, E-mail: dib2015@qatar-med.cornell.edu [Weil Cornell Medical College in Qatar, Qatar Foundation-Education City, P.O. Box 24144, Doha (Qatar)

2011-03-15

Platinum complexes are clinically used as adjuvant therapy of cancers aiming to induce tumor cell death. Depending on cell type and concentration, cisplatin induces cytotoxicity, e.g., by interference with transcription and/or DNA replication mechanisms. Additionally, cisplatin damages tumors via induction of apoptosis, mediated by the activation of various signal transduction pathways, including calcium signaling, death receptor signaling, and the activation of mitochondrial pathways. Unfortunately, neither cytotoxicity nor apoptosis are exclusively induced in cancer cells, thus, cisplatin might also lead to diverse side-effects such as neuro- and/or renal-toxicity or bone marrow-suppression. Moreover, the binding of cisplatin to proteins and enzymes may modulate its biochemical mechanism of action. While a combination-chemotherapy with cisplatin is a cornerstone for the treatment of multiple cancers, the challenge is that cancer cells could become cisplatin-resistant. Numerous mechanisms of cisplatin resistance were described including changes in cellular uptake, drug efflux, increased detoxification, inhibition of apoptosis and increased DNA repair. To minimize cisplatin resistance, combinatorial therapies were developed and have proven more effective to defeat cancers. Thus, understanding of the biochemical mechanisms triggered by cisplatin in tumor cells may lead to the design of more efficient platinum derivates (or other drugs) and might provide new therapeutic strategies and reduce side effects.

Castration of piglets under CO2-gas anaesthesia.

Science.gov (United States)

Gerritzen, M A; Kluivers-Poodt, M; Reimert, H G M; Hindle, V; Lambooij, E

2008-11-01

It has become common practice in pig fattening production systems to castrate young boar piglets without the use of anaesthesia. In this study, we examined whether or not CO2 gas is capable of inducing an acceptable anaesthetic state during which castration can be performed. The first step was to identify the most promising CO2/O2 mixture. Based on the results from this first experiment, a mixture of 70% CO2 + 30% O2 was chosen for further investigation as a potential anaesthetic during the castration of young piglets. Thereby, it was established whether the duration and depth of anaesthesia were acceptable for castration where the animal has to be insensible and unconscious. Physiological effects were assessed based on electroencephalogram (EEG) and electrocardiogram (ECG) measurements, blood gas values and behavioural responses. During the induction phase, the only typical behaviour the piglets exhibited when exposed to the 70/30 gas mixture was heavy breathing. All piglets (n = 25) lost consciousness after approximately 30 s according to the EEG. Heart rate decreased slowly during the induction phase, a serious drop occurred when piglets lost their posture. Immediately after this drop, the heart rate neared zero or showed a very irregular pattern. Shortly after loss of posture, most animals showed a few convulsions. None of the animals showed any reaction to castration in behaviour and/or on the EEG and ECG. On average, the piglets recovered within 59 s, i.e. EEG returned to its pre-induction pattern and piglets were able to regain a standing position. After 120 s, heart rate returned to pre-induction levels. In order to explore the usage range of CO2 concentration, 24 piglets were exposed to 60% CO2 + 20% O2 + 20% N2 for up to 30 s after loss of consciousness (as registered on EEG), and castrated after removal from the chamber. Sixteen of the 24 animals showed a reaction to the castration on the EEG. To establish the maximum time piglets survive in 70% CO2 + 30

Radiographic progression with nonrising PSA in metastatic castration-resistant prostate cancer: post hoc analysis of PREVAIL.

Science.gov (United States)

Bryce, A H; Alumkal, J J; Armstrong, A; Higano, C S; Iversen, P; Sternberg, C N; Rathkopf, D; Loriot, Y; de Bono, J; Tombal, B; Abhyankar, S; Lin, P; Krivoshik, A; Phung, D; Beer, T M

2017-06-01

Advanced prostate cancer is a phenotypically diverse disease that evolves through multiple clinical courses. PSA level is the most widely used parameter for disease monitoring, but it has well-recognized limitations. Unlike in clinical trials, in practice, clinicians may rely on PSA monitoring alone to determine disease status on therapy. This approach has not been adequately tested. Chemotherapy-naive asymptomatic or mildly symptomatic men (n=872) with metastatic castration-resistant prostate cancer (mCRPC) who were treated with the androgen receptor inhibitor enzalutamide in the PREVAIL study were analyzed post hoc for rising versus nonrising PSA (empirically defined as >1.05 vs ⩽1.05 times the PSA level from 3 months earlier) at the time of radiographic progression. Clinical characteristics and disease outcomes were compared between the rising and nonrising PSA groups. Of 265 PREVAIL patients with radiographic progression and evaluable PSA levels on the enzalutamide arm, nearly one-quarter had a nonrising PSA. Median progression-free survival in this cohort was 8.3 months versus 11.1 months in the rising PSA cohort (hazard ratio 1.68; 95% confidence interval 1.26-2.23); overall survival was similar between the two groups, although less than half of patients in either group were still at risk at 24 months. Baseline clinical characteristics of the two groups were similar. Non-rising PSA at radiographic progression is a common phenomenon in mCRPC patients treated with enzalutamide. As restaging in advanced prostate cancer patients is often guided by increases in PSA levels, our results demonstrate that disease progression on enzalutamide can occur without rising PSA levels. Therefore, a disease monitoring strategy that includes imaging not entirely reliant on serial serum PSA measurement may more accurately identify disease progression.

Antitumour Activity and Safety of Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer Previously Treated with Abiraterone Acetate Plus Prednisone for ≥24 weeks in Europe.

Science.gov (United States)

de Bono, Johann S; Chowdhury, Simon; Feyerabend, Susan; Elliott, Tony; Grande, Enrique; Melhem-Bertrandt, Amal; Baron, Benoit; Hirmand, Mohammad; Werbrouck, Patrick; Fizazi, Karim

2018-07-01

Enzalutamide and abiraterone acetate plus prednisone, which target the androgen receptor axis, have expanded the treatment of advanced prostate cancer. Retrospective analyses suggest some cross-resistance between these two drugs when used sequentially, but robust, prospective studies have not yet been reported. To fulfil a regulatory postregistration commitment by evaluating the efficacy and safety of enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) who progressed following abiraterone acetate plus prednisone treatment. Multicentre, single-arm, open-label study, enrolled patients with progressing mCRPC after ≥24 wk of abiraterone acetate plus prednisone treatment. All patients maintained castration therapy during the trial. Prior chemotherapy was allowed but not required. Patients received enzalutamide 160mg/d orally. The primary endpoint was radiographic progression-free survival. Secondary endpoints were overall survival, prostate-specific antigen (PSA) response, and time-to-PSA progression. Safety data were also assessed. Kaplan-Meier methods were used to descriptively analyse time-to-event endpoints. Overall, 214 patients received enzalutamide treatment, 145 of whom were chemotherapy-naïve. Median radiographic progression-free survival was 8.1 mo (95% confidence interval: 6.1-8.3); median overall survival had not been reached. Unconfirmed PSA response rate was 27% (48 of 181). Median time-to-PSA progression was 5.7 mo (95% confidence interval: 5.6-5.8). The most common treatment-emergent adverse events were fatigue (32%), decreased appetite (25%), asthenia (18%), back pain (17%), and arthralgia (16%). No seizures were reported. Enzalutamide showed antitumour activity in some patients with mCRPC who had previously progressed following ≥24 wk of abiraterone acetate plus prednisone treatment. Patients with mCRPC who progressed on previous abiraterone acetate plus prednisone treatment, with or without prior chemotherapy

Depression of nocturnal pineal serotonin N-acetyltransferase activity in castrate male rats

International Nuclear Information System (INIS)

Rudeen, P.K.; Reiter, R.J.; Texas Univ., San Antonio

1980-01-01

Pineal serotonin N-acetyltransferase (NAT) activity was examined in intact rats, castrated rats, and in rats that had been castrated and had received testosterone proprionate. Castration resulted in significantly depressing nocturnal levels of pineal NAT (p<0.05) when compared to enzyme activity in intact rats. Testosterone proprionate administration restored plasma LH levels to normal values in castrate rats but did not induce nocturnal pineal enzyme activity to levels seen in the pineal glands of intact rats. The data substantiate the existence of a feedback control of pineal biosynthetic activity by the hypophyseal-gonadal system, but the identity of the hormone(s) responsible for regulation of pineal NAT activity is not known. (author)

Testosterone improves erectile function through inhibition of reactive oxygen species generation in castrated rats

Directory of Open Access Journals (Sweden)

Rui Li

2016-05-01

Full Text Available Testosterone is overwhelmingly important in regulating erectile physiology. However, the associated molecular mechanisms are poorly understood. The purpose of this study was to explore the effects and mechanisms of testosterone in erectile dysfunction (ED in castrated rats. Forty male Sprague-Dawley rats were randomized to four groups (control, sham-operated, castration and castration-with-testosterone-replacement. Reactive oxygen species (ROS production was measured by dihydroethidium (DHE staining. Erectile function was assessed by the recording of intracavernous pressure (ICP and mean arterial blood pressure (MAP. Protein expression levels were examined by western blotting. We found that castration reduced erectile function and that testosterone restored it. Nitric oxide synthase (NOS activity was decrease in the castrated rats, and testosterone administration attenuated this decrease (each p < 0.05. The testosterone, dihydrotestosterone, cyclic guanosine monophosphate (cGMP and cyclic adenosine monophosphate (cAMP concentrations were lower in the castrated rats, and testosterone restored these levels (each p < 0.05. Furthermore, the cyclooxygenase-2 (COX-2 and prostacyclin synthase (PTGIS expression levels and phospho-endothelial nitric oxide synthase (p-eNOS, Ser1177/endothelial nitric oxide synthase (eNOS ratio were reduced in the castrated rats compared with the controls (each p < 0.05. In addition, the p40phox and p67phox expression levels were increased in the castrated rats, and testosterone reversed these changes (each p < 0.05. Overall, our results demonstrate that testosterone ameliorates ED after castration by reducing ROS production and increasing the activity of the eNOS/cGMP and COX-2/PTGIS/cAMP signaling pathways.

Sensitivity to ionizing radiation and chemotherapeutic agents in gemcitabine-resistant human tumor cell lines

International Nuclear Information System (INIS)

Bree, Chris van; Kreder, Natasja Castro; Loves, Willem J.P.; Franken, Nicolaas A.P.; Peters, Godefridus J.; Haveman, Jaap

2002-01-01

Purpose: To determine cross-resistance to anti-tumor treatments in 2',2'difluorodeoxycytidine (dFdC, gemcitabine)-resistant human tumor cells. Methods and Materials: Human lung carcinoma cells SW-1573 (SWp) were made resistant to dFdC (SWg). Sensitivity to cisplatin (cDDP), paclitaxel, 5-fluorouracil (5-FU), methotrexate (MTX), cytarabine (ara-C), and dFdC was measured by a proliferation assay. Radiosensitivity and radioenhancement by dFdC of this cell panel and the human ovarian carcinoma cell line A2780 and its dFdC-resistant variant AG6000 were determined by clonogenic assay. Bivariate flowcytometry was performed to study cell cycle changes. Results: In the SWg, a complete deoxycytidine kinase (dCK) deficiency was found on mRNA and protein level. This was accompanied by a 10-fold decrease in dCK activity which resulted in the >1000-fold resistance to dFdC. Sensitivity to other anti-tumor drugs was not altered, except for ara-C (>100-fold resistance). Radiosensitivity was not altered in the dFdC-resistant cell lines SWg and AG6000. High concentrations (50-100 μM dFdC) induced radioenhancement in the dFdC-resistant cell lines similar to the radioenhancement obtained at lower concentrations (10 nM dFdC) in the parental lines. An early S-phase arrest was found in all cell lines after dFdC treatment where radioenhancement was achieved. Conclusions: In the dFdC-resistant lung tumor cell line SWg, the deficiency in dCK is related to the resistance to dFdC and ara-C. No cross-resistance was observed to other anti-tumor drugs used for the treatment in lung cancer. Sensitivity to ionizing radiation was not altered in two different dFdC-resistant cell lines. Resistance to dFdC does not eliminate the ability of dFdC to sensitize cells to radiation

Assessment and management of pain associated with castration in cattle.

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Coetzee, Johann F

2013-03-01

Validated pain assessment tools are needed to support approval of analgesic compounds to alleviate pain associated with castration. Accelerometers, videography, heart rate variability, electroencephalography, thermography, and plasma neuropeptide measurement to assess behavioral, physiologic, and neuroendocrine changes associated with castration are discussed. Preemptive local and systemic analgesia are also reviewed. Previous studies found that preemptive administration of nonsteroidal antiinflammatory drug (NSAID) and local anesthesia significantly decreased peak serum cortisol concentration after castration. Local anesthesia alone tended to decrease peak cortisol concentrations more than NSAIDs, whereas NSAIDs alone tended to decrease the area under the cortisol-time curve more than local anesthesia alone. Copyright © 2013 Elsevier Inc. All rights reserved.

Differential thermo-resistance of multicellular tumor spheroids

International Nuclear Information System (INIS)

Khoei, S.; Goliaei, B.; Neshasteh-Rize, A.

2004-01-01

Many cell lines, when cultured under proper conditions, can form three dimensional structures called multicellular spheroids. These spheroids resemble in vivo tumor models in several aspects. Therefore, studying growth characteristics and behavior of spheroids is beneficial in understanding the behavior of tumors under various experimental conditions. In this work, we have studied the growth properties, along with the thermal characteristics of spheroids of Du 145 human prostate carcinoma cell lines and compared the results to monolayer cultures of these cells. For this purpose, The Du 145 cells were cultured either as monolayer or spheroids. At various times after initiation of cultures, the growth properties of spheroids as a function of seeding cell number was determined. To evaluate the thermal characteristics of spheroids, they were heated at various stages of growth at 43 d ig c for various periods. The thermal response was judged by the survival fraction of colony forming cells in spheroids or monolayer culture following heat treatment. The results showed spheroids were more resistant to heat than monolayer cultures at all stages of development. However, the extent of this thermal resistant was dependent on the age, and consequently, the size of the spheroid. The result suggests that the differential thermal resistance of the spheroid cultures develop gradually during the growth of spheroid cultures of Du 145 cell line

MAIN MOLECULAR TARGETS FOR PROSTATE CANCER THERAPY

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G. S. Krasnov

2014-01-01

Full Text Available Androgenic pathway plays a pivotal role in the development of benign and malignant prostate tumors. Most of the prostate neoplasms are hormone-dependent at the time of diagnosis. Therapeutic interventions aimed at reducing the level of testosterone in the blood allow to stop progression of the disease. But over time, the tumor almost inevitably starts to progress, moving in the castration-resistant state (CRPC, representing a serious problem of oncourology. In recent years, the possibility of CRRPC therapy increased significantly – there was developed a number of new drugs that effectively inhibit the development of castration-resistant tumors and significantly push back the start of chemotherapy. This review describes the major drug targets and mechanisms of action of abiraterone, enzalutamide, galeterone, VT-464 and other approved and promising CRPC therapies.

The evolution of intermediate castration virulence and ant coexistence in a spatially structured environment.

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Szilágyi, András; Scheuring, István; Edwards, David P; Orivel, Jerome; Yu, Douglas W

2009-12-01

Theory suggests that spatial structuring should select for intermediate levels of virulence in parasites, but empirical tests are rare and have never been conducted with castration (sterilizing) parasites. To test this theory in a natural landscape, we construct a spatially explicit model of the symbiosis between the ant-plant Cordia nodosa and its two, protecting ant symbionts, Allomerus and Azteca. Allomerus is also a castration parasite, preventing fruiting to increase colony fecundity. Limiting the dispersal of Allomerus and host plant selects for intermediate castration virulence. Increasing the frequency of the mutualist, Azteca, selects for higher castration virulence in Allomerus, because seeds from Azteca-inhabited plants are a public good that Allomerus exploits. These results are consistent with field observations and, to our knowledge, provide the first empirical evidence supporting the hypothesis that spatial structure can reduce castration virulence and the first such evidence in a natural landscape for either mortality or castration virulence.

Vimentin and Ki67 expression in circulating tumour cells derived from castrate-resistant prostate cancer.

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Lindsay, C R; Le Moulec, S; Billiot, F; Loriot, Y; Ngo-Camus, M; Vielh, P; Fizazi, K; Massard, C; Farace, F

2016-02-29

High circulating tumor cell (CTC) counts are associated with poor prognosis in advanced prostate cancer, and recently CTC number was suggested to be a surrogate for survival in metastatic castrate-resistant prostate cancer (mCRPC). Ki67 and vimentin are well-characterised markers of tumour cell proliferation and the epithelial-mesenchymal transition (EMT), respectively. Here we asked if the expression of vimentin and Ki67 in CTCs offered prognostic or predictive information in mCRPC. In two separate patient cohorts, anti-vimentin or anti-Ki67 antibodies were added to the free channel in the CellSearch® system for analysis of peripheral blood samples. For each cohort, association of CTC number with clinical characteristics were assessed using Fisher's exact, Mann-Whitney and chi-squared tests. Kaplan-Meier method and log-rank tests were used to analyse overall survival (OS) of vimentin-expressing and Ki67-expressing CTC patient cohorts. In this retrospective analysis, CTC vimentin expression was analysed in 142 blood samples from 93 patients, and CTC Ki67 expression was analysed in 90 blood samples from 51 patients. In the vimentin cohort, 80/93 (86 %) of baseline samples from patients were CTC-positive overall (≥1 total CTC per 7.5 mls blood), and 30/93 (32.3 %) vimentin CTC-positive (≥1 vimentin-positive CTC per 7.5 mls blood). 41/51 (80.4 %) of baseline samples from patients in the Ki67 cohort were CTC-positive overall, and 23/51 (45.1 %) Ki67 CTC-positive (≥1 Ki67-positive CTC per 7.5 mls blood). There was no significant difference in baseline PSA in patients with vimentin-positive CTC at baseline versus those with no vimentin-positive CTC at baseline (p = 0.33). A significant reduction in OS was shown in patients with vimentin-positive CTC compared to those without vimentin-positive CTC (median 305 days vs 453 days, p = 0.0293). There was no significant difference in baseline PSA in patients with Ki67-positive CTC at baseline versus those without Ki67

Vimentin and Ki67 expression in circulating tumour cells derived from castrate-resistant prostate cancer

International Nuclear Information System (INIS)

Lindsay, C. R.; Le Moulec, S.; Billiot, F.; Loriot, Y.; Ngo-Camus, M.; Vielh, P.; Fizazi, K.; Massard, C.; Farace, F.

2016-01-01

High circulating tumor cell (CTC) counts are associated with poor prognosis in advanced prostate cancer, and recently CTC number was suggested to be a surrogate for survival in metastatic castrate-resistant prostate cancer (mCRPC). Ki67 and vimentin are well-characterised markers of tumour cell proliferation and the epithelial-mesenchymal transition (EMT), respectively. Here we asked if the expression of vimentin and Ki67 in CTCs offered prognostic or predictive information in mCRPC. In two separate patient cohorts, anti-vimentin or anti-Ki67 antibodies were added to the free channel in the CellSearch® system for analysis of peripheral blood samples. For each cohort, association of CTC number with clinical characteristics were assessed using Fisher’s exact, Mann-Whitney and chi-squared tests. Kaplan-Meier method and log-rank tests were used to analyse overall survival (OS) of vimentin-expressing and Ki67-expressing CTC patient cohorts. In this retrospective analysis, CTC vimentin expression was analysed in 142 blood samples from 93 patients, and CTC Ki67 expression was analysed in 90 blood samples from 51 patients. In the vimentin cohort, 80/93 (86 %) of baseline samples from patients were CTC-positive overall (≥1 total CTC per 7.5 mls blood), and 30/93 (32.3 %) vimentin CTC-positive (≥1 vimentin-positive CTC per 7.5 mls blood). 41/51 (80.4 %) of baseline samples from patients in the Ki67 cohort were CTC-positive overall, and 23/51 (45.1 %) Ki67 CTC-positive (≥1 Ki67-positive CTC per 7.5 mls blood). There was no significant difference in baseline PSA in patients with vimentin-positive CTC at baseline versus those with no vimentin-positive CTC at baseline (p = 0.33). A significant reduction in OS was shown in patients with vimentin-positive CTC compared to those without vimentin-positive CTC (median 305 days vs 453 days, p = 0.0293). There was no significant difference in baseline PSA in patients with Ki67-positive CTC at baseline versus those without Ki67

Anakoinosis: Communicative Reprogramming of Tumor Systems - for Rescuing from Chemorefractory Neoplasia.

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Hart, Christina; Vogelhuber, Martin; Wolff, Daniel; Klobuch, Sebastian; Ghibelli, Lina; Foell, Jürgen; Corbacioglu, Selim; Rehe, Klaus; Haegeman, Guy; Thomas, Simone; Herr, Wolfgang; Reichle, Albrecht

2015-08-01

Disruptive technologies, such as communicative reprogramming (anakoinosis) with cellular therapies in situ for treating refractory metastatic cancer allow patient care to accelerate along a totally new trajectory and highlight what may well become the next sea change in the care of patients with many types of advanced neoplasia. Cellular therapy in situ consisted of repurposed drugs, pioglitazone plus all-trans retinoic acid or dexamethasone or interferon-alpha (dual transcriptional modulation) combined with metronomic low-dose chemotherapy or low-dose 5-azacytidine, plus/minus classic targeted therapy. The novel therapeutic tools for specifically designing communication processes within tumor diseases focus on redirecting (1) rationalizations of cancer hallmarks (constitution of single cancer hallmarks), (2) modular events, (3) the 'metabolism' of evolutionary processes (the sum of therapeutically and intrinsically inducible evolutionary processes) and (4) the holistic communicative context, which determines validity and denotation of tumor promoting communication lines. Published data on cellular therapies in situ (6 histologic tumor types, 144 patients, age 0.9-83 years) in castration-resistant prostate cancer, pretreated renal clear cell carcinoma, chemorefractory acute myelocytic leukemia, multiple myeloma > second-line, chemorefractory Hodgkin lymphoma or multivisceral Langerhans cell histiocytosis, outline the possibility for treating refractory metastatic cancer with the hope that this type of reprogrammed communication will be scalable with minimal toxicity. Accessibility to anakoinosis is a tumor inherent feature, and cellular therapy in situ addresses extrinsic and intrinsic drug resistance, by redirecting convergent organized communication tools, while been supported by quite different pattern of (molecular-)genetic aberrations.

Routine castration in 568 draught colts: incidence of evisceration and omental herniation.

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Shoemaker, R; Bailey, J; Janzen, E; Wilson, D G

2004-05-01

Castration is one of the most common routine surgical procedures performed in the horse, from which a number of potential complications can arise. We undertook a prospective evaluation of short-term complications associated with castration of draught colts over a 3-year period (1998-2000). To compare castration complications in a large number of draught foals with previously published literature. Five hundred and sixty-eight draught colts, age 4 or 5 months, were castrated in field conditions. Foals were observed for complications for 24 h post operatively. There was no significant difference in complication rates between open and closed surgical techniques. Inguinal/scrotal hernia rate was 4.6% (26/568) prior to surgery, and evisceration of the small intestine occurred in 4.8% (27/568). Foals observed to eviscerate underwent immediate surgical correction with an overall survival rate of 72.2% (13/18). Omental herniation was seen in 2.8% (16/568) of colts. This study showed no difference between the closed and open techniques of castration and the rate of omental herniation or evisceration. The evisceration rate in combination with the omental and presurgical herniation rates approached 12.2%, which is high enough to warrant further examination. Future investigation should help to assess predisposing factors for evisceration. Regardless of the technique employed, herniation appears to pose a significant risk to draught foals undergoing castration.

Overcoming tumor resistance by heterologous adeno-poxvirus combination therapy

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Markus Vähä-Koskela

2014-01-01

Full Text Available Successful cancer control relies on overcoming resistance to cell death and on activation of host antitumor immunity. Oncolytic viruses are particularly attractive in this regard, as they lyse infected tumor cells and trigger robust immune responses during the infection. However, repeated injections of the same virus promote antiviral rather than antitumor immunity and tumors may mount innate antiviral defenses to restrict oncolytic virus replication. In this article, we have explored if alternating the therapy virus could circumvent these problems. We demonstrate in two virus-resistant animal models a substantial delay in antiviral immune- and innate cellular response induction by alternating injections of two immunologically distinct oncolytic viruses, adenovirus, and vaccinia virus. Our results are in support of clinical development of heterologous adeno-/vaccinia virus therapy of cancer.

SU-D-303-01: Spatial Distribution of Bone Metastases In Metastatic Castrate-Resistant Prostate Cancer

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Perk, T; Bradshaw, T; Harmon, S; Perlman, S; Liu, G; Jeraj, R [University of Wisconsin, Madison, WI (United States)

2015-06-15

Purpose: Identification of metastatic bone lesions is critical in prostate cancer, where treatments may be more effective in patients with fewer lesions. This study aims characterize the distribution and spread of bone lesions and create a probability map of metastatic spread in bone. Methods: Fifty-five metastatic castrate-resistant prostate cancer patients received up to 3 whole-body [F-18]NaF PET/CT scans. Lesions were identified by physician on PET/CT and contoured using a threshold of SUV>15. An atlas-based segmentation method was used to create CT regions, which determined skeletal location of lesions. Patients were divided into 3 groups with low (N<40), medium (40100) numbers of lesions. A combination of articulated and deformable registrations was used to register the skeletal segments and lesions of each patient to a single skeleton. All the lesion data was then combined to make a probability map. Results: A total of 4038 metastatic lesions (mean 74, range 2–304) were identified. Skeletal regions with highest occurrence of lesions included ribs, thoracic spine, and pelvis with 21%, 19%, and 15% of the total number lesions and 8%, 18%, and 31 % of the total lesion volume, respectively. Interestingly, patients with fewer lesions were found to have a lower proportion of lesions in the ribs (9% in low vs. 27% in high number of lesions). Additionally, the probability map showed specific areas in the spine and pelvis where over 75% of patients had metastases, and other areas in the skeleton with a less than 2% of metastases. Conclusion: We identified skeletal regions with higher incidence of metastases and specific sub-regions in the skeleton that had high or low probability of occurrence of metastases. Additionally, we found that metastatic lesions in the ribs and skull occur more commonly in advanced disease. These results may have future applications in computer-aided diagnosis. Funding from the Prostate Cancer Foundation.

Effect of tasting and information on consumer opinion about pig castration

NARCIS (Netherlands)

Kallas, Z.; Gil, J.M.; Panella-Riera, N.; Blanch, M.; Furnols, M.F.I.; Chevillon, P.; Roest, de K.; Tacken, G.M.L.; Oliver, M.A.

2013-01-01

Our research explored the relative importance of pig castration amongst other aspects of animal welfare, and the potential impact of information and sensory experiences on European Union (EU) consumers' preferences. The EU is considering a future ban on surgical pig castration by 2018 which may

Androgen Receptor Splice Variants and Resistance to Taxane Chemotherapy

Science.gov (United States)

2017-10-01

resistant prostate cancer ; docetaxel; cabazitaxel; chemotherapy; androgen receptor splice variants; microtubule; ligand-binding domain; microtubule... receptor splice variants (AR-Vs) are associated with resistance to taxane chemotherapy in castration- resistant prostate cancer (CRPC). However, this...androgen receptor inhibitors in prostate cancer . Nat Rev Cancer . 2015;15:701–11.

Lactate dehydrogenase predicts combined progression-free survival after sequential therapy with abiraterone and enzalutamide for patients with castration-resistant prostate cancer.

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Mori, Keiichiro; Kimura, Takahiro; Onuma, Hajime; Kimura, Shoji; Yamamoto, Toshihiro; Sasaki, Hiroshi; Miki, Jun; Miki, Kenta; Egawa, Shin

2017-07-01

An array of clinical issues remains to be resolved for castration-resistant prostate cancer (CRPC), including the sequence of drug use and drug cross-resistance. At present, no clear guidelines are available for the optimal sequence of use of novel agents like androgen-receptor axis-targeted (ARAT) agents, particularly enzalutamide, and abiraterone. This study retrospectively analyzed a total of 69 patients with CRPC treated with sequential therapy using enzalutamide followed by abiraterone or vice versa. The primary outcome measure was the comparative combined progression-free survival (PFS) comprising symptomatic and/or radiographic PFS. Patients were also compared for total prostate-specific antigen (PSA)-PFS, overall survival (OS), and PSA response. The predictors of combined PFS and OS were analyzed with a backward-stepwise multivariate Cox model. Of the 69 patients, 46 received enzalutamide first, followed by abiraterone (E-A group), and 23 received abiraterone, followed by enzalutamide (A-E group). The two groups were not significantly different with regard to basic data, except for hemoglobin values. In a comparison with the E-A group, the A-E group was shown to be associated with better combined PFS in Kaplan-Meier analysis (P = 0.043). Similar results were obtained for total PSA-PFS (P = 0.049), while OS did not differ between groups (P = 0.62). Multivariate analysis demonstrated that pretreatment lactate dehydrogenase (LDH) values and age were significant predictors of longer combined PFS (P < 0.05). Likewise, multivariate analysis demonstrated that pretreatment hemoglobin values and performance status were significant predictors of longer OS (P < 0.05). The results of this study suggested the A-E sequence had longer combined PSA and total PSA-PFS compared to the E-A sequence in patients with CRPC. LDH values in sequential therapy may serve as a predictor of longer combined PFS. © 2017 Wiley Periodicals, Inc.

Radiographic Progression-Free Survival as a Clinically Meaningful End Point in Metastatic Castration-Resistant Prostate Cancer: The PREVAIL Randomized Clinical Trial.

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Rathkopf, Dana E; Beer, Tomasz M; Loriot, Yohann; Higano, Celestia S; Armstrong, Andrew J; Sternberg, Cora N; de Bono, Johann S; Tombal, Bertrand; Parli, Teresa; Bhattacharya, Suman; Phung, De; Krivoshik, Andrew; Scher, Howard I; Morris, Michael J

2018-05-01

Drug development for metastatic castration-resistant prostate cancer has been limited by a lack of clinically relevant trial end points short of overall survival (OS). Radiographic progression-free survival (rPFS) as defined by the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) is a candidate end point that represents a clinically meaningful benefit to patients. To demonstrate the robustness of the PCWG2 definition and to examine the relationship between rPFS and OS. PREVAIL was a phase 3, randomized, double-blind, placebo-controlled multinational study that enrolled 1717 chemotherapy-naive men with metastatic castration-resistant prostate cancer from September 2010 through September 2012. The data were analyzed in November 2016. Patients were randomized 1:1 to enzalutamide 160 mg or placebo until confirmed radiographic disease progression or a skeletal-related event and initiation of either cytotoxic chemotherapy or an investigational agent for prostate cancer treatment. Sensitivity analyses (SAs) of investigator-assessed rPFS were performed using the final rPFS data cutoff (May 6, 2012; 439 events; SA1) and the interim OS data cutoff (September 16, 2013; 540 events; SA2). Additional SAs using investigator-assessed rPFS from the final rPFS data cutoff assessed the impact of skeletal-related events (SA3), clinical progression (SA4), a confirmatory scan for soft-tissue disease progression (SA5), and all deaths regardless of time after study drug discontinuation (SA6). Correlations between investigator-assessed rPFS (SA2) and OS were calculated using Spearman ρ and Kendall τ via Clayton copula. In the 1717 men (mean age, 72.0 [range, 43.0-93.0] years in enzalutamide arm and 71.0 [range, 42.0-93.0] years in placebo arm), enzalutamide significantly reduced risk of radiographic progression or death in all SAs, with hazard ratios of 0.22 (SA1; 95% CI, 0.18-0.27), 0.31 (SA2; 95% CI, 0.27-0.35), 0.21 (SA3; 95% CI, 0.18-0.26), 0.21 (SA4; 95% CI, 0.17-0.26), 0

Clinical Outcomes from Androgen Signaling-directed Therapy after Treatment with Abiraterone Acetate and Prednisone in Patients with Metastatic Castration-resistant Prostate Cancer: Post Hoc Analysis of COU-AA-302.

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Smith, Matthew R; Saad, Fred; Rathkopf, Dana E; Mulders, Peter F A; de Bono, Johann S; Small, Eric J; Shore, Neal D; Fizazi, Karim; Kheoh, Thian; Li, Jinhui; De Porre, Peter; Todd, Mary B; Yu, Margaret K; Ryan, Charles J

2017-07-01

In the COU-AA-302 trial, abiraterone acetate plus prednisone significantly increased overall survival for patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC). Limited information exists regarding response to subsequent androgen signaling-directed therapies following abiraterone acetate plus prednisone in patients with mCRPC. We investigated clinical outcomes associated with subsequent abiraterone acetate plus prednisone (55 patients) and enzalutamide (33 patients) in a post hoc analysis of COU-AA-302. Prostate-specific antigen (PSA) response was assessed. Median time to PSA progression was estimated using the Kaplan-Meier method. The PSA response rate (≥50% PSA decline, unconfirmed) was 44% and 67%, respectively. The median time to PSA progression was 3.9 mo (range 2.6-not estimable) for subsequent abiraterone acetate plus prednisone and 2.8 mo (range 1.8-not estimable) for subsequent enzalutamide. The majority of patients (68%) received intervening chemotherapy before subsequent abiraterone acetate plus prednisone or enzalutamide. While acknowledging the limitations of post hoc analyses and high censoring (>75%) in both treatment groups, these results suggest that subsequent therapy with abiraterone acetate plus prednisone or enzalutamide for patients who progressed on abiraterone acetate is associated with limited clinical benefit. This analysis showed limited clinical benefit for subsequent abiraterone acetate plus prednisone or enzalutamide in patients with metastatic castration-resistant prostate cancer following initial treatment with abiraterone acetate plus prednisone. This analysis does not support prioritization of subsequent abiraterone acetate plus prednisone or enzalutamide following initial therapy with abiraterone acetate plus prednisone. Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Exploring the Role of BET Bromodomain Proteins in AR Transcriptional Regulation: A Perpetuating Cycle of JQ1 Resistance in CRPC Therapy

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2016-12-01

Risk Gene in Metastatic Prostate Cancers with Novel Epigenetic Inhibitors. May19-20, 2016  What do you plan to do during the next reporting... Epigenetic Regulation of HOXB13 Transcriptional Networks Promotes Castration Resistant Prostate Cancer Growth (Manuscript under preparation...Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT During the inevitable progression to castration resistant stage, prostate cancer

Effect of castration method and analgesia on inflammation, behavior, growth performance, and carcass traits in feedlot cattle.

Science.gov (United States)

Roberts, S L; Powell, J G; Hughes, H D; Richeson, J T

2018-02-15

Our objective was to determine the effect of castration timing, method, and use of the analgesic meloxicam (MEL) on inflammation, behavior, performance, and carcass traits in feedlot cattle. This study was a randomized complete block design conducted over a 3-yr period. In total, 194 crossbred beef calves from a single ranch origin were randomized at birth to receive one of five treatments arranged as a 2 × 2 + 1 factorial: 1) bulls castrated within 48 h of birth (CON), 2) bulls surgically castrated on day 0 without MEL (SUR), 3) bulls surgically castrated on day 0 with MEL (SUR + MEL), 4) bulls band castrated on d 0 without MEL (BAN), and 5) bulls band castrated on day 0 with MEL (BAN + MEL). Upon feedlot arrival (day -11; average 287 ± 2.03 d of age), animals were blocked by initial BW (224 ± 4.5 kg) and assigned randomly to treatment pens in three consecutive years (n = 2 pens per treatment in each year). Oral MEL was administered at 1 mg/kg BW concurrent with applicable castration treatment on day 0. Data were analyzed using the MIXED and GLIMMIX procedures of SAS with pen (year) serving as experimental unit. From days 0 to 7, ADG was reduced (P = 0.01) for surgical (-0.42) compared to band (0.43 kg/d) castration. Conversely, ADG was increased for surgical (1.74) vs. band (1.46 kg/d) castration from days 14 to 32. There was also an overall (day 0 to final) improvement in ADG for MEL (P = 0.02), but no effect of castration method was observed (P = 0.81). The CON group had the greatest (P = 0.05) marbling score. Backfat thickness was increased (P = 0.01) for MEL. A treatment × day interaction (P = 0.04) existed for serum haptoglobin, with SUR having the greatest (P castrated treatment reduced (P = 0.01) serum haptoglobin concentration on day 1. Relative to baseline, standing duration for surgical castration was increased 113 min (P castration on day 0. Step count was greatest for BAN, intermediate for CON, and least for surgical (P castration, whereas

Differential effects of androgens on coronary blood flow regulation and arteriolar diameter in intact and castrated swine

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O’Connor Erin K

2012-05-01

Full Text Available Abstract Background Low endogenous testosterone levels have been shown to be a risk factor for the development of cardiovascular disease and cardiovascular benefits associated with testosterone replacement therapy are being advocated; however, the effects of endogenous testosterone levels on acute coronary vasomotor responses to androgen administration are not clear. The objective of this study was to compare the effects of acute androgen administration on in vivo coronary conductance and in vitro coronary microvascular diameter in intact and castrated male swine. Methods Pigs received intracoronary infusions of physiologic levels (1–100 nM of testosterone, the metabolite 5α-dihydrotestosterone, and the epimer epitestosterone while left anterior descending coronary blood flow and mean arterial pressure were continuously monitored. Following sacrifice, coronary arterioles were isolated, cannulated, and exposed to physiologic concentrations (1–100 nM of testosterone, 5α-dihydrotestosterone, and epitestosterone. To evaluate effects of the androgen receptor on acute androgen dilation responses, real-time PCR and immunohistochemistry for androgen receptor were performed on conduit and resistance coronary vessels. Results In vivo, testosterone and 5α-dihydrotestosterone produced greater increases in coronary conductance in the intact compared to the castrated males. In vitro, percent maximal dilation of microvessels was similar between intact and castrated males for testosterone and 5α-dihydrotestosterone. In both studies epitestosterone produced significant increases in conductance and microvessel diameter from baseline in the intact males. Androgen receptor mRNA expression and immunohistochemical staining were similar in intact and castrated males. Conclusions Acute coronary vascular responses to exogenous androgen administration are increased by endogenous testosterone, an effect unrelated to changes in androgen receptor expression.

A Continuation Study Using Sunitinib Malate For Patients Leaving Treatment On A Previous Sunitinib Study.

Science.gov (United States)

2015-10-07

Metastatic Breast Cancer [F]; Advanced Breast Cancer; Metastatic Castration Resistant Prostate Cancer; Metastatic Renal Cell Cancer; Non-Small Cell Lung Cancer; Thyroid Cancer; Advanced/Metastatic Non-Small Cell Lung Cancer; Advanced Gastric Cancer; Gastrointestinal Stromal Tumor; Hepatocellular Carcinoma; Pancreatic Islet Cell Carcinoma; Pancreatic Neuroendocrine Tumor

Effects of castration method and frequency of intramuscular injections of ketoprofen on behavioral and physiological indicators of pain in beef cattle.

Science.gov (United States)

Moya, D; González, L A; Janzen, E; Caulkett, N A; Fireheller, E; Schwartzkopf-Genswein, K S

2014-04-01

Two experiments were conducted to determine the effect of a single or multiple intramuscular (i.m.) injection of ketoprofen and castration technique on physiological and behavioral indicators of pain in beef calves. A total of 150 bull calves (284.8 ± 22.7 kg BW) were used in both experiments, each 1 conducted as a 3 × 2 factorial design, where main factors included castration technique--no castration (CT), surgical (SU), or band (BA)--and drug administration--physiological solution (PS) or i.m. injection of ketoprofen (KP; 3 mg Anafen/kg BW) in the neck of calves. Animals were weighed weekly during the experiment to calculate ADG. Behavioral responses indicative of pain and discomfort during the castration procedure were documented using a visual analog score (VAS) by an experienced observer who was blind to the treatments. Movements of the animals in the chute during castration were quantified using a strain gauge system mounted on the head gate to evaluate the escape response of the cattle. Pens were equipped with an automated feed bunk monitoring system enabling feed intake and feeding behavior to be continuously monitored for each individual. Thermographic images of the scrotal area were evaluated 24 and 0.5 h before castration, 0.5, 1, 24, 48, and 270 h postcastration, and weekly thereafter until the end of the trial. Blood samples were obtained postcastration to evaluate changes in total white blood cell (WBC) count and neutrophil-to-lymphocyte (N:L) ratio. Saliva samples were taken 24 and 0.5 h before castration, immediately after castration, and 0.5, 1, 2, 5, 24, and 48 h and then 5, 7, and 14 d after castration to determine cortisol concentration. Scrotal temperature, VAS, total WBC, N:L ratio, salivary cortisol, mobility, and pressure exerted in the chute were greater (P castration. Also, BA calves had a greater (P castration and a lower feed intake and ADG at wk 2 and 3 and wk 6 and 7 after castration, respectively, compared to CT. Treatment KP had

Shifting paradigms in the estimation of survival for castration-resistant prostate cancer: A tertiary academic center experience.

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Afshar, Mehran; Evison, Felicity; James, Nicholas D; Patel, Prashant

2015-08-01

Castration-resistant prostate cancer (CRPC) has retained a guarded prognosis, with historical survival estimates of 18 to 24 months. However, the landscape of available therapy has changed, and the emphasis has altered from supportive to active treatment. Few large series from real-world populations exist in the contemporary era with fully mature survival data to confirm the indication based on clinical trials that patients with CRPC are surviving far longer than the historical estimates. We aim to review a large patient cohort with CRPC and provide mature survival data. Using the electronic histopathology database at Queen Elizabeth Hospital, Birmingham, UK, all prostate-specific antigentest results between April 2006 and September 2007 were extracted, and patients satisfying the American Society for Radiation Oncology (ASTRO) definition of hormone failure were identified. Electronic records were reviewed and variables were collected, including survival, treatment, biochemistry, histopathology, and demographics. Probability of survival, and of developing metastasis or CRPC, was determined using the Kaplan-Meier method. Patients were stratified into 3 groups, namely, D0--no metastasis at diagnosis but later appearance, D1--no metastasis at diagnosis or at last follow-up, and D2--metastasis at diagnosis. From 8,062 patient-prostate-specific antigen episodes, we identified 447 patients meeting the criteria. A notes review revealed 147 patients with CRPC. Median overall survival (OS) from diagnosis was 84.7 months (95% CI: 73-89), and 129 deaths had occurred (88%). Median OS from diagnosis for D0, D1, and D2 patients was 100.4, 180.1, and 58.9 months, respectively (Pdata benefit clinicians and patients in understanding prognosis and treatment choices. Importantly, our patients were diagnosed before the current wave of novel therapeutics for CRPC, so survival for men diagnosed today may be more than our findings. Copyright © 2015 Elsevier Inc. All rights reserved.

Accuracy of serum luteinizing hormone and serum testosterone measurements to assess the efficacy of medical castration in prostate cancer patients.

Science.gov (United States)

Morote, Juan; Comas, Imma; Ferrer, Roser; Planas, Jacques; Celma, Anna; Regis, Lucas

2017-10-22

Luteinizing hormone-releasing hormone (LH-RH) agonists are the standard for androgen deprivation therapy (ADT) in prostate cancer (PCa) patients. Current guidelines recommend serum testosterone measurement to assess the efficacy of ADT and to define castration resistance. However, serum testosterone does not reflect the exclusive effect of castration due to its extratesticular production. The aim of this study is to analyze if serum LH reflects better than serum testosterone the activity of LH-RH agonists. Serum LH and serum testosterone were measured with chemiluminescent immunoassay (CLIA) in a cohort study of 1091 participants: 488 PCa patients "on LH-RH agonists", 303 "off LH-RH agonist" in whom LH-RH agonists were withdrawn, and 350 men with PCa suspicion "no LH-RH agonist" who never received LH-RH agonists. In a validation cohort of 147 PCa patients, 124 on "LH-RH agonists" and 19 "off LH-RH agonists", serum testosterone was also measured with liquid chromatography and tandem mass spectrometry (LC MSMS). The area under the curve (AUC) to distinguish patients "on versus off LH-RH agonists" was 0.997 for serum LH and 0.740 for serum testosterone, P < 0.001. The 97.5 percentile of serum LH in patients "on LH-RH agonists" was 0.97 U/L, been the most efficient threshold 1.1 U/L. The AUCs for serum LH, testosterone measured with CLIA and with LC MSMS, in the validation cohort, were respectively 1.000, 0.646 and 0.814, P < 0.001. The efficacy to distinguish patients "on versus off LH-RH agonists" was 98.6%, 78.3%, and 89.5% respectively, using 1.1 U/L as threshold for serum LH and 50 ng/dL for serum testosterone regardless the method. Serum LH is more accurate than serum testosterone regardless the method, to distinguish patients "on versus off LH-RH agonists". The castrate level of serum LH is 1.1 U/l. These findings suggest that assessment of LH-RH agonist efficacy and castration resistance definition should be reviewed.

A novel rabbit anti-hepatocyte growth factor monoclonal neutralizing antibody inhibits tumor growth in prostate cancer cells and mouse xenografts

International Nuclear Information System (INIS)

Yu, Yanlan; Chen, Yicheng; Ding, Guoqing; Wang, Mingchao; Wu, Haiyang; Xu, Liwei; Rui, Xuefang; Zhang, Zhigen

2015-01-01

The hepatocyte growth factor and its receptor c-Met are correlated with castration-resistance in prostate cancer. Although HGF has been considered as an attractive target for therapeutic antibodies, the lack of cross-reactivity of monoclonal antibodies with human/mouse HGFs is a major obstacle in preclinical developments. We generated a panel of anti-HGF RabMAbs either blocking HGF/c-Met interaction or inhibiting c-Met phosphorylation. We selected one RabMAb with mouse cross-reactivity and demonstrated that it blocked HGF-stimulated downstream activation in PC-3 and DU145 cells. Anti-HGF RabMAb inhibited not only the growth of PC-3 cells but also HGF-dependent proliferation in HUVECs. We further demonstrated the efficacy and potency of the anti-HGF RabMAb in tumor xenograft mice models. Through these in vitro and in vivo experiments, we explored a novel therapeutic antibody for advanced prostate cancer. - Highlights: • HGF is an attractive target for castration-refractory prostate cancer. • We generated and characterized a panel of anti-HGF rabbit monoclonal antibodies. • More than half of these anti-HGF RabMAbs was cross-reactive with mouse HGF. • Anti-HGF RabMAb blocks HGF-stimulated phosphorylation and cell growth in vitro. • Anti-HGF RabMAb inhibits tumor growth and angiogenesis in xenograft mice

A novel rabbit anti-hepatocyte growth factor monoclonal neutralizing antibody inhibits tumor growth in prostate cancer cells and mouse xenografts

Energy Technology Data Exchange (ETDEWEB)

Yu, Yanlan; Chen, Yicheng; Ding, Guoqing; Wang, Mingchao; Wu, Haiyang; Xu, Liwei; Rui, Xuefang; Zhang, Zhigen, E-mail: srrshurology@163.com

2015-08-14

The hepatocyte growth factor and its receptor c-Met are correlated with castration-resistance in prostate cancer. Although HGF has been considered as an attractive target for therapeutic antibodies, the lack of cross-reactivity of monoclonal antibodies with human/mouse HGFs is a major obstacle in preclinical developments. We generated a panel of anti-HGF RabMAbs either blocking HGF/c-Met interaction or inhibiting c-Met phosphorylation. We selected one RabMAb with mouse cross-reactivity and demonstrated that it blocked HGF-stimulated downstream activation in PC-3 and DU145 cells. Anti-HGF RabMAb inhibited not only the growth of PC-3 cells but also HGF-dependent proliferation in HUVECs. We further demonstrated the efficacy and potency of the anti-HGF RabMAb in tumor xenograft mice models. Through these in vitro and in vivo experiments, we explored a novel therapeutic antibody for advanced prostate cancer. - Highlights: • HGF is an attractive target for castration-refractory prostate cancer. • We generated and characterized a panel of anti-HGF rabbit monoclonal antibodies. • More than half of these anti-HGF RabMAbs was cross-reactive with mouse HGF. • Anti-HGF RabMAb blocks HGF-stimulated phosphorylation and cell growth in vitro. • Anti-HGF RabMAb inhibits tumor growth and angiogenesis in xenograft mice.

Castration modulates singing patterns and electrophysiological properties of RA projection neurons in adult male zebra finches

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Songhua Wang

2014-04-01

Full Text Available Castration can change levels of plasma testosterone. Androgens such as testosterone play an important role in stabilizing birdsong. The robust nucleus of the arcopallium (RA is an important premotor nucleus critical for singing. In this study, we investigated the effect of castration on singing patterns and electrophysiological properties of projection neurons (PNs in the RA of adult male zebra finches. Adult male zebra finches were castrated and the changes in bird song assessed. We also recorded the electrophysiological changes from RA PNs using patch clamp recording. We found that the plasma levels of testosterone were significantly decreased, song syllable’s entropy was increased and the similarity of motif was decreased after castration. Spontaneous and evoked firing rates, membrane time constants, and membrane capacitance of RA PNs in the castration group were lower than those of the control and the sham groups. Afterhyperpolarization AHP time to peak of spontaneous action potential (AP was prolonged after castration.These findings suggest that castration decreases song stereotypy and excitability of RA PNs in male zebra finches.

Analytical Validation and Clinical Qualification of a New Immunohistochemical Assay for Androgen Receptor Splice Variant-7 Protein Expression in Metastatic Castration-resistant Prostate Cancer.

Science.gov (United States)

Welti, Jonathan; Rodrigues, Daniel Nava; Sharp, Adam; Sun, Shihua; Lorente, David; Riisnaes, Ruth; Figueiredo, Ines; Zafeiriou, Zafeiris; Rescigno, Pasquale; de Bono, Johann S; Plymate, Stephen R

2016-10-01

The androgen receptor splice variant-7 (AR-V7) has been implicated in the development of castration-resistant prostate cancer (CRPC) and resistance to abiraterone and enzalutamide. To develop a validated assay for detection of AR-V7 protein in tumour tissue and determine its expression and clinical significance as patients progress from hormone-sensitive prostate cancer (HSPC) to CRPC. Following monoclonal antibody generation and validation, we retrospectively identified patients who had HSPC and CRPC tissue available for AR-V7 immunohistochemical (IHC) analysis. Nuclear AR-V7 expression was determined using IHC H score (HS) data. The change in nuclear AR-V7 expression from HSPC to CRPC and the association between nuclear AR-V7 expression and overall survival (OS) was determined. Nuclear AR-V7 expression was significantly lower in HSPC (median HS 50, interquartile range [IQR] 17.5-90) compared to CRPC (HS 135, IQR 80-157.5; pprostate cancer. A higher level of AR-V7 identifies a group of patients who respond less well to certain prostate cancer treatments and live for a shorter period of time. Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Cost-effectiveness of abiraterone treatment in patients with castration-resistant prostate cancer who previously received docetaxel therapy

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A. V. Rudakova

2014-01-01

Full Text Available Background. Therapy for metastatic castration-resistant prostate cancer (CRPC is a serious problem that requires significant public health care expenditures.Objective: to evaluate the cost-effectiveness of abiraterone treatment in patients with metastatic CRPC who previously received docetaxel under the conditions of the budgetary public health system of the Russian Federation.Material and methods. Markovian simulation based on the COU-AA-301 randomized placebo-controlled Phase III study was used. Survival analysis was made in 70-year-old patients. The cost of abiraterone therapy corresponded to that of the 2013 auctions.Results. Abiraterone therapy in patients who have previously received docetaxel therapy causes an increase in average life expectancy by an average of 4.6 months and progression-free survival by 2.0 months. Moreover, the cost calculated with reference to one year of additional life will account for about 3.6 million rubles and that to one additional quality-adjusted life year will be about 5.45 million rubles.Conclusion. The cost-effectiveness of abiraterone therapy for metastatic CRPC in patients who have previously received docetaxel therapy is similar to that of other medicaments used in oncological practice under the conditions of the budgetary public health system of the Russian Federation. In this connection, abiraterone may be considered as an economically acceptable medical intervention in this clinical situation.

Cost-effectiveness of abiraterone treatment in patients with castration-resistant prostate cancer who previously received docetaxel therapy

Directory of Open Access Journals (Sweden)

A. V. Rudakova

2014-11-01

Full Text Available Background. Therapy for metastatic castration-resistant prostate cancer (CRPC is a serious problem that requires significant public health care expenditures.Objective: to evaluate the cost-effectiveness of abiraterone treatment in patients with metastatic CRPC who previously received docetaxel under the conditions of the budgetary public health system of the Russian Federation.Material and methods. Markovian simulation based on the COU-AA-301 randomized placebo-controlled Phase III study was used. Survival analysis was made in 70-year-old patients. The cost of abiraterone therapy corresponded to that of the 2013 auctions.Results. Abiraterone therapy in patients who have previously received docetaxel therapy causes an increase in average life expectancy by an average of 4.6 months and progression-free survival by 2.0 months. Moreover, the cost calculated with reference to one year of additional life will account for about 3.6 million rubles and that to one additional quality-adjusted life year will be about 5.45 million rubles.Conclusion. The cost-effectiveness of abiraterone therapy for metastatic CRPC in patients who have previously received docetaxel therapy is similar to that of other medicaments used in oncological practice under the conditions of the budgetary public health system of the Russian Federation. In this connection, abiraterone may be considered as an economically acceptable medical intervention in this clinical situation.

Self-castration by a transsexual woman: financial and psychological costs: a case report.

Science.gov (United States)

St Peter, Matthew; Trinidad, Anton; Irwig, Michael S

2012-04-01

The out-of-pocket cost for an elective orchiectomy, which is often not covered by health insurance, is a significant barrier to male-to-female transsexuals ready to proceed with their physical transition. This and other barriers (lack of access to a surgeon willing to perform the operation, waiting times, and underlying psychological and psychiatric conditions) lead a subset of transsexual women to attempt self-castration. Little information has been published on the financial costs and implications of self-castration to both patients and health care systems. We compare the financial and psychological costs of elective surgical orchiectomy vs. self-castration in the case of a transsexual woman in her 40s. We interviewed the patient and her providers and obtained financial information from local reimbursement and billing specialists. After experiencing minor hemorrhage following the self-castration, our patient presented to the emergency department and underwent a bilateral inguinal exploration, ligation and removal of bilateral spermatic cords, and complicated scrotal exploration, debridement, and closure. She was admitted to the psychiatric service for a hospital stay of three days. The total bill was U.S. $14,923, which would compare with U.S. $4,000 for an elective outpatient orchiectomy in the patient's geographical area. From a financial standpoint, an elective orchiectomy could have cost the health care system significantly less than a hospital admission with its associated additional costs. From a patient safety standpoint, elective orchiectomy is preferable to self-castration which carries significant risks such as hemorrhage, disfigurement, infection, urinary fistulae, and nerve damage. Healthcare providers of transsexual women should carefully explore patient attitudes toward self-castration and work toward improving access to elective orchiectomy to reduce the number of self-castrations and costs to the overall health care system. Further research on the

Downregulation of androgen receptors by NaAsO2 via 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

Cytotoxicity of the indole alkaloid reserpine from Rauwolfia serpentina against drug-resistant tumor cells.

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Abdelfatah, Sara A A; Efferth, Thomas

2015-02-15

The antihypertensive reserpine is an indole alkaloid from Rauwolfia serpentina and exerts also profound activity against cancer cells in vitro and in vivo. The present investigation was undertaken to investigate possible modes of action to explain its activity toward drug-resistant tumor cells. Sensitive and drug-resistant tumor cell lines overexpressing P-glycoprotein (ABCB1/MDR1), breast cancer resistance protein (ABCG2/BCRP), mutation-activated epidermal growth factor receptor (EGFR), wild-type and p53-knockout cells as well as the NCI panel of cell lines from different tumor origin were analyzed. Reserpine's cytotoxicity was investigated by resazurin and sulforhodamine assays, flow cytometry, and COMPARE and hierarchical cluster analyses of transcriptome-wide microarray-based RNA expressions. P-glycoprotein- or BCRP overexpressing tumor cells did not reveal cross-resistance to reserpine. EGFR-overexpressing cells were collateral sensitive and p53- Knockout cells cross-resistant to this drug compared to their wild-type parental cell lines. Reserpine increased the uptake of doxorubicin in P-glycoprotein-overexpressing cells, indicating that reserpine inhibited the efflux function of P-glycoprotein. Using molecular docking, we found that reserpine bound with even higher binding energy to P-glycoprotein and EGFR than the control drugs verapamil (P-glycoprotein inhibitor) and erlotinib (EGFR inhibitor). COMPARE and cluster analyses of microarray data showed that the mRNA expression of a panel of genes predicted the sensitivity or resistance of the NCI tumor cell line panel with statistical significance. The genes belonged to diverse pathways and biological functions, e.g. cell survival and apoptosis, EGFR activation, regulation of angiogenesis, cell mobility, cell adhesion, immunological functions, mTOR signaling, and Wnt signaling. The lack of cross-resistance to most resistance mechanisms and the collateral sensitivity in EGFR-transfectants compared to wild

Effects of age/weight and castration on fatty acids composition in ...

African Journals Online (AJOL)

This study investigates the effects of age/weight and castration on the fatty acid composition and the qualities of pork and pork fat. Thirty hybrid male pigs (50% Meishan x 50% Large White) were used. Fifteen were castrated within the first two days of age and the other fifteen remained entire. At 12 weeks of age, the pigs ...

Effect of anti-gonadotropin-releasing factor vaccine and band castration on indicators of welfare in beef cattle.

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Marti, S; Devant, M; Amatayakul-Chantler, S; Jackson, J A; Lopez, E; Janzen, E D; Schwartzkopf-Genswein, K S

2015-04-01

Angus crossbred bulls (n = 60; 257 ± 5.4 d of age; initial BW 358.8 ± 3.78 kg) were used to study the effect of a vaccine against gonadotropin-releasing factor (GnRF) and band castration on behavioral and physiological indicators of pain. Cattle were randomly assigned to 1 of 3 treatments: bulls, band-castrated calves without pain mitigation (castrated), and immune-vaccinated animals administered an anti-GnRF vaccine (vaccinated). All animals were fitted with a radio frequency ear tag so that individual animal feed intake and feeding behavior were recorded daily over the entire trial using an electronic feed bunk monitoring system. Two doses of anti-GnRF vaccine were administrated on d -35 and 0 and band castration was performed on d 0. Animal BW was recorded weekly starting on d -36 until d 56. Visual analog scores (VAS) were measured on d -36 -35, -1, and 0, and salivary cortisol concentration was measured at -30, 0, 30, 60, 120, and 270 min on d -35 and 0 after castration. Saliva and blood were obtained on d 1, 2, 5, and 7 and weekly until d 56 for determination of cortisol and complete blood cell count. Video data were collected for pain, sexual, and aggressive behavior daily the first week and once a week until d 56. Data were analyzed with a mixed-effect model with castration, time, and their interactions as main effects. Vaccinated calves had reduced ADG and intake (P castrated calves had reduced ADG and intake (P castration. However, on d 0, castrated cattle had greater cortisol concentrations and VAS (P 0.05) between treatments on d 0, 1, and 2. At d 56, vaccinated calves had greater (P castrated calves and both had less final BW than bulls. There was no indication that vaccination caused any physiological or behavioral changes indicative of pain. In contrast, band castration resulted in elevated cortisol scores and VAS indicative of a pain response and behavior related to pain (P castration in beef cattle under North American feedlot practices.

Effects of Castration on Expression of Lipid Metabolism Genes in the Liver of Korean Cattle

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Baik, Myunggi; Nguyen, Trang Hoa; Jeong, Jin Young; Piao, Min Yu; Kang, Hyeok Joong

2015-01-01

Castration induces the accumulation of body fat and deposition of intramuscular fat in Korean cattle, resulting in improved beef quality. However, little is known about the metabolic adaptations in the liver following castration. To understand changes in lipid metabolism following castration, hepatic expression levels of lipid metabolism genes were compared between Korean bulls and steers. Steers had higher (p

Stimulation of cytolytic T lymphocytes by azaguanine-resistant mouse tumor cells in selective hat medium

International Nuclear Information System (INIS)

Snick, J. van; Uyttenhove, C.; Pel, A. van; Boon, T.

1981-01-01

Primed syngeneic or umprimed allogeneic mouse spleen cells were stimulated with azaguanine-resistant P815 tumor cells that were killed by the addition of aminopterin to the stimulation medium. The recovery of lymphocytes and their cytolytic activity and specificity were similar to those obtained after stimulation with irradiated cells. This method conveniently replaces the inactivation of stimulatory cells by irradiation or mitomycin treatment. Moreover, it has the advantage of inactivating not only the stimulatory cells but also the tumor cells that often contaminate the spleens of tumor-bearing animals, provided these animals have been inoculated with azaguanine-resistant tumor cell mutants. (Auth.)

Severe hypoxia induces chemo-resistance in clinical cervical tumors through MVP over-expression.

Science.gov (United States)

Lara, Pedro C; Lloret, Marta; Clavo, Bernardino; Apolinario, Rosa M; Henríquez-Hernández, Luis Alberto; Bordón, Elisa; Fontes, Fausto; Rey, Agustín

2009-08-06

Oxygen molecule modulates tumour response to radiotherapy. Higher radiation doses are required under hypoxic conditions to induce cell death. Hypoxia may inhibit the non-homologous end-joining DNA repair through down regulating Ku70/80 expression. Hypoxia induces drug resistance in clinical tumours, although the mechanism is not clearly elucidated. Vaults are ribonucleoprotein particles with a hollow barrel-like structure composed of three proteins: major vault protein (MVP), vault poly(ADP-ribose) polymerase, and telomerase associated protein-1 and small untranslated RNA. Over-expression of MVP has been associated with chemotherapy resistance. Also, it has been related to poor outcome in patients treated with radiotherapy alone. The aim of the present study was to assess the relation of Major Vault Protein expression and tumor hypoxia in clinical cervical tumors. MVP, p53 and angiogenesis, together with tumor oxygenation, were determined in forty-three consecutive patients suffering from localized cervix carcinoma. High MVP expression was related to severe hypoxia compared to low MVP expressing tumors (p = 0.022). Tumors over-expressing MVP also showed increased angiogenesis (p = 0.003). Besides it, in this study we show for the first time that severe tumor hypoxia is associated with high MVP expression in clinical cervical tumors. Up-regulation of MVP by hypoxia is of critical relevance as chemotherapy is currently a standard treatment for those patients. From our results it could be suggested that hypoxia not only induces increased genetic instability, oncogenic properties and metastatization, but through the correlation observed with MVP expression, another pathway of chemo and radiation resistance could be developed.

Severe hypoxia induces chemo-resistance in clinical cervical tumors through MVP over-expression

International Nuclear Information System (INIS)

Lara, Pedro C; Lloret, Marta; Clavo, Bernardino; Apolinario, Rosa M; Henríquez-Hernández, Luis Alberto; Bordón, Elisa; Fontes, Fausto; Rey, Agustín

2009-01-01

Oxygen molecule modulates tumour response to radiotherapy. Higher radiation doses are required under hypoxic conditions to induce cell death. Hypoxia may inhibit the non-homologous end-joining DNA repair through down regulating Ku70/80 expression. Hypoxia induces drug resistance in clinical tumours, although the mechanism is not clearly elucidated. Vaults are ribonucleoprotein particles with a hollow barrel-like structure composed of three proteins: major vault protein (MVP), vault poly(ADP-ribose) polymerase, and telomerase associated protein-1 and small untranslated RNA. Over-expression of MVP has been associated with chemotherapy resistance. Also, it has been related to poor outcome in patients treated with radiotherapy alone. The aim of the present study was to assess the relation of Major Vault Protein expression and tumor hypoxia in clinical cervical tumors. MVP, p53 and angiogenesis, together with tumor oxygenation, were determined in forty-three consecutive patients suffering from localized cervix carcinoma. High MVP expression was related to severe hypoxia compared to low MVP expressing tumors (p = 0.022). Tumors over-expressing MVP also showed increased angiogenesis (p = 0.003). Besides it, in this study we show for the first time that severe tumor hypoxia is associated with high MVP expression in clinical cervical tumors. Up-regulation of MVP by hypoxia is of critical relevance as chemotherapy is currently a standard treatment for those patients. From our results it could be suggested that hypoxia not only induces increased genetic instability, oncogenic properties and metastatization, but through the correlation observed with MVP expression, another pathway of chemo and radiation resistance could be developed

Nanoparticle-mediated combination chemotherapy and photodynamic therapy overcomes tumor drug resistance in vitro.

Science.gov (United States)

Khdair, Ayman; Handa, Hitesh; Mao, Guangzhao; Panyam, Jayanth

2009-02-01

Drug resistance limits the success of many anticancer drugs. Reduced accumulation of the drug at its intracellular site of action because of overexpression of efflux transporters such as P-glycoprotein (P-gp) is a major mechanism of drug resistance. In this study, we investigated whether photodynamic therapy (PDT) using methylene blue, also a P-gp inhibitor, can be used to enhance doxorubicin-induced cytotoxicity in drug-resistant tumor cells. Aerosol OT (AOT)-alginate nanoparticles were used as a carrier for the simultaneous cellular delivery of doxorubicin and methylene blue. Methylene blue was photoactivated using light of 665 nm wavelength. Induction of apoptosis and necrosis following treatment with combination chemotherapy and PDT was investigated in drug-resistant NCI/ADR-RES cells using flow cytometry and fluorescence microscopy. Effect of encapsulation in nanoparticles on the intracellular accumulation of doxorubicin and methylene blue was investigated qualitatively using fluorescence microscopy and was quantitated using HPLC. Encapsulation in AOT-alginate nanoparticles significantly enhanced the cytotoxicity of combination therapy in resistant tumor cells. Nanoparticle-mediated combination therapy resulted in a significant induction of both apoptosis and necrosis. Improvement in cytotoxicity could be correlated with enhanced intracellular and nuclear delivery of the two drugs. Further, nanoparticle-mediated combination therapy resulted in significantly elevated reactive oxygen species (ROS) production compared to single drug treatment. In conclusion, nanoparticle-mediated combination chemotherapy and PDT using doxorubicin and methylene blue was able to overcome resistance mechanisms and resulted in improved cytotoxicity in drug-resistant tumor cells.

Drug resistance following irradiation of RIF-1 tumors: Influence of the interval between irradiation and drug treatment

International Nuclear Information System (INIS)

Hopwood, L.E.; Davies, B.M.; Moulder, J.E.

1990-01-01

RIF-1 tumors contain a small number of cells (1 to 100 per 10(6) cells) that are resistant to 5-fluorouracil, methotrexate, or adriamycin. The frequency of drug-resistant cells among individual untreated tumors is highly variable. Radiation, delivered in vivo at doses of 3 to 12 Gy, increases the frequency of methotrexate- and 5-fluorouracil-resistant cells, but not the frequency of adriamycin-resistant cells. The magnitude of induction of 5-fluorouracil and methotrexate resistance shows a complex dependence on the radiation dose and on the interval between irradiation and assessment of drug resistance. For a dose of 3 Gy, induced 5-fluorouracil and methotrexate resistance is seen only after an interval of 5 to 7 days, whereas for a dose of 12 Gy, high levels of induced resistance are observed 1 to 3 days after irradiation. The maximum absolute risk for induction of resistance is 4 per 10(4) cells per Gy for methotrexate, and 3 per 10(6) cells per Gy for 5-fluorouracil. These results indicate that tumor hypoxia may play a role in the increased levels of drug resistance seen after irradiation, and that both genetic and environmental factors may influence radiation-induction of drug resistance. These studies provide essential data for models of the development of tumor drug resistance, and imply that some of the drug resistance seen when chemotherapy follows radiotherapy may be caused by radiation-induced drug resistance

Effects of Topical Anaesthetic and Buccal Meloxicam Treatments on Concurrent Castration and Dehorning of Beef Calves

Directory of Open Access Journals (Sweden)

Dominique Van der Saag

2018-02-01

Full Text Available The use of pain relief during castration and dehorning of calves on commercial beef operations can be limited by constraints associated with the delivery of analgesic agents. As topical anaesthetic (TA and buccal meloxicam (MEL are now available in Australia, offering practical analgesic treatments for concurrent castration and dehorning of beef calves, a study was conducted to determine their efficacy in providing pain relief when applied separately or in combination. Weaner calves were randomly allocated to; (1 no castration and dehorning/positive control (CONP; (2 castration and dehorning/negative control (CONN; (3 castration and dehorning with buccal meloxicam (BM; (4 castration and dehorning with topical anaesthetic (TA; and (5 castration and dehorning with buccal meloxicam and topical anaesthetic (BMTA. Weight gain, paddock utilisation, lying activity and individual behaviours following treatment were measured. CONP and BMTA calves had significantly greater weight gain than CONN calves (p < 0.001. CONN calves spent less time lying compared to BMTA calves on all days (p < 0.001. All dehorned and castrated calves spent more time walking (p = 0.024 and less time eating (p < 0.001 compared to CONP calves. There was a trend for CONP calves to spend the most time standing and CONN calves to spend the least time standing (p = 0.059. There were also trends for the frequency of head turns to be lowest in CONP and BMTA calves (p = 0.098 and tail flicks to be highest in CONN and BM calves (p = 0.061. The findings of this study suggest that TA and MEL can potentially improve welfare and production of calves following surgical castration and amputation dehorning.

Circular RNA alterations are involved in resistance to avian leukosis virus subgroup-J-induced tumor formation in chickens.

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Zhang, Xinheng; Yan, Yiming; Lei, Xiaoya; Li, Aijun; Zhang, Huanmin; Dai, Zhenkai; Li, Xinjian; Chen, Weiguo; Lin, Wencheng; Chen, Feng; Ma, Jingyun; Xie, Qingmei

2017-05-23

Avian leukosis virus subgroup (ALV-J) is an oncogenic neoplasm-inducing retrovirus that causes significant economic losses in the poultry industry. Recent studies have demonstrated circular RNAs (circRNAs) are implicated in pathogenic processes; however, no research has indicated circRNAs are involved in resistance to disease. In this study, over 1800 circRNAs were detected by circRNA sequencing of liver tissues from ALV-J-resistant (n = 3) and ALV-J-susceptible chickens (n = 3). 32 differentially expressed circRNAs were selected for analyzing including 12 upregulated in ALV-J-resistant chickens and 20 upregulated in ALV-J-susceptible chickens, besides, the top five microRNAs (miRNAs) for 12 upregulated circRNAs in ALV-J-resistant chickens were analyzed. Gene ontology and KEGG pathway analyses were performed for miRNA target genes, the predicted genes were mainly involved in immune pathways. This study provides the first evidence that circRNA alterations are involved in resistance to ALV-J-induced tumor formation. We propose circRNAs may help to mediate tumor induction and development in chickens.

Comparative study of 2 surgical techniques for castration of guinea pigs (Cavia porcellus).

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Guilmette, Josée; Langlois, Isabelle; Hélie, Pierre; El Warrak, Alexander de Oliveira

2015-10-01

The objective of this study was to compare 2 surgical approaches (scrotal or abdominal) for castration of guinea pigs and to investigate post-operative infection rates with either technique. Forty-eight guinea pigs were castrated by scrotal or abdominal technique after being randomly assigned to 1 of 2 groups (n = 24). Individuals were either castrated by an experienced exotic animal surgeon (n = 12) or by an experienced small animal surgeon (n = 12). Surgical wounds were evaluated daily before euthanasia for histological evaluation 2 wks after surgery. Post-operative infection rate was significantly higher in the scrotal group than in the abdominal group, with a higher rate for the experienced small animal surgeon. Castration of guinea pigs with the abdominal technique is significantly faster and has a significantly lower post-operative infection rate than the scrotal technique.

TMPRSS2- driven ERG expression in vivo increases self-renewal and maintains expression in a castration resistant subpopulation.

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Orla M Casey

Full Text Available Genomic rearrangements commonly occur in many types of cancers and often initiate or alter the progression of disease. Here we describe an in vivo mouse model that recapitulates the most frequent rearrangement in prostate cancer, the fusion of the promoter region of TMPRSS2 with the coding region of the transcription factor, ERG. A recombinant bacterial artificial chromosome including an extended TMPRSS2 promoter driving genomic ERG was constructed and used for transgenesis in mice. TMPRSS2-ERG expression was evaluated in tissue sections and FACS-fractionated prostate cell populations. In addition to the anticipated expression in luminal cells, TMPRSS2-ERG was similarly expressed in the Sca-1(hi/EpCAM(+ basal/progenitor fraction, where expanded numbers of clonogenic self-renewing progenitors were found, as assayed by in vitro sphere formation. These clonogenic cells increased intrinsic self renewal in subsequent generations. In addition, ERG dependent self-renewal and invasion in vitro was demonstrated in prostate cell lines derived from the model. Clinical studies have suggested that the TMPRSS2-ERG translocation occurs early in prostate cancer development. In the model described here, the presence of the TMPRSS2-ERG fusion alone was not transforming but synergized with heterozygous Pten deletion to promote PIN. Taken together, these data suggest that one function of TMPRSS2-ERG is the expansion of self-renewing cells, which may serve as targets for subsequent mutations. Primary prostate epithelial cells demonstrated increased post transcriptional turnover of ERG compared to the TMPRSS2-ERG positive VCaP cell line, originally isolated from a prostate cancer metastasis. Finally, we determined that TMPRSS2-ERG expression occurred in both castration-sensitive and resistant prostate epithelial subpopulations, suggesting the existence of androgen-independent mechanisms of TMPRSS2 expression in prostate epithelium.

Ectopic expression of X-linked lymphocyte-regulated protein pM1 renders tumor cells resistant to antitumor immunity.

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Kang, Tae Heung; Noh, Kyung Hee; Kim, Jin Hee; Bae, Hyun Cheol; Lin, Ken Y; Monie, Archana; Pai, Sara I; Hung, Chien-Fu; Wu, T-C; Kim, Tae Woo

2010-04-15

Tumor immune escape is a major obstacle in cancer immunotherapy, but the mechanisms involved remain poorly understood. We have previously developed an immune evasion tumor model using an in vivo immune selection strategy and revealed Akt-mediated immune resistance to antitumor immunity induced by various cancer immunotherapeutic agents. In the current study, we used microarray gene analysis to identify an Akt-activating candidate molecule overexpressed in immune-resistant tumors compared with parental tumors. X-linked lymphocyte-regulated protein pM1 (XLR) gene was the most upregulated in immune-resistant tumors compared with parental tumor cells. Furthermore, the retroviral transduction of XLR in parental tumor cells led to activation of Akt, resulting in upregulation of antiapoptotic proteins and the induction of immune resistance phenotype in parental tumor cells. In addition, we found that transduction of parental tumor cells with other homologous genes from the mouse XLR family, such as synaptonemal complex protein 3 (SCP3) and XLR-related, meiosis-regulated protein (XMR) and its human counterpart of SCP3 (hSCP3), also led to activation of Akt, resulting in the upregulation of antiapoptotic proteins and induction of immune resistance phenotype. Importantly, characterization of a panel of human cervical cancers revealed relatively higher expression levels of hSCP3 in human cervical cancer tissue compared with normal cervical tissue. Thus, our data indicate that ectopic expression of XLR and its homologues in tumor cells represents a potentially important mechanism for tumor immune evasion and serves as a promising molecular target for cancer immunotherapy. (c) 2010 AACR.

Testosterone Depletion by Castration May Protect Mice from Heat-Induced Multiple Organ Damage and Lethality

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Ruei-Tang Cheng

2010-01-01

Full Text Available When the vehicle-treated, sham-operated mice underwent heat stress, the fraction survival and core temperature at +4 h of body heating were found to be 5 of 15 and 34.4∘C±0.3∘C, respectively. Castration 2 weeks before the start of heat stress decreased the plasma levels of testosterone almost to zero, protected the mice from heat-induced death (fraction survival, 13/15 and reduced the hypothermia (core temperature, 37.3∘C. The beneficial effects of castration in ameliorating lethality and hypothermia can be significantly reduced by testosterone replacement. Heat-induced apoptosis, as indicated by terminal deoxynucleotidyl- transferase- mediatedαUDP-biotin nick end-labeling staining, were significantly prevented by castration. In addition, heat-induced neuronal damage, as indicated by cell shrinkage and pyknosis of nucleus, to the hypothalamus was also castration-prevented. Again, the beneficial effects of castration in reducing neuronal damage to the hypothalamus as well as apoptosis in multiple organs during heatstroke, were significantly reversed by testosterone replacement. The data indicate that testosterone depletion by castration may protect mice from heatstroke-induced multiple organ damage and lethality.

Down-regulation of DNA mismatch repair proteins in human and murine tumor spheroids: implications for multicellular resistance to alkylating agents.

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Francia, Giulio; Green, Shane K; Bocci, Guido; Man, Shan; Emmenegger, Urban; Ebos, John M L; Weinerman, Adina; Shaked, Yuval; Kerbel, Robert S

2005-10-01

Similar to other anticancer agents, intrinsic or acquired resistance to DNA-damaging chemotherapeutics is a major obstacle for cancer therapy. Current strategies aimed at overcoming this problem are mostly based on the premise that tumor cells acquire heritable genetic mutations that contribute to drug resistance. Here, we present evidence for an epigenetic, tumor cell adhesion-mediated, and reversible form of drug resistance that is associated with a reduction of DNA mismatch repair proteins PMS2 and/or MLH1 as well as other members of this DNA repair process. Growth of human breast cancer, human melanoma, and murine EMT-6 breast cancer cell lines as multicellular spheroids in vitro, which is associated with increased resistance to many chemotherapeutic drugs, including alkylating agents, is shown to lead to a reproducible down-regulation of PMS2, MLH1, or, in some cases, both as well as MHS6, MSH3, and MSH2. The observed down-regulation is in part reversible by treatment of tumor spheroids with the DNA-demethylating agent, 5-azacytidine. Thus, treatment of EMT-6 mouse mammary carcinoma spheroids with 5-azacytidine resulted in reduced and/or disrupted cell-cell adhesion, which in turn sensitized tumor spheroids to cisplatin-mediated killing in vitro. Our results suggest that antiadhesive agents might sensitize tumor spheroids to alkylating agents in part by reversing or preventing reduced DNA mismatch repair activity and that the chemosensitization properties of 5-azacytidine may conceivably reflect its role as a potential antiadhesive agent as well as reversal agent for MLH1 gene silencing in human tumors.

[Painful procedures in small ruminants - castration of rams and bucks. - An overview].

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Bauer, Benjamin; Hannemann, Regina; Lendl, Christine; Strobel, Heinz; Ganter, Martin

2018-04-01

The castration of farm animals is practiced routinely throughout the world and the procedure is subject to different levels of regulation in different countries. In Germany, painful procedures in animals are regulated by the animal welfare act. However, the indications for acceptable methods of lamb and kid castration are still under discussion. There are distinct differences between the theoretical requirements of this legislation and experiences in practice. When male lambs are kept for many months with their dams, or with ewe lambs, castration is essential to avoid unwanted pregnancies and the slaughter of pregnant females. In the opinion of the authors, it is essential that castration of small ruminants must remain possible. However, the methods used for these painful procedures need to be reassessed and if necessary new regulations established. When castration is necessary, sufficient anaesthesia and analgesia must be used irrespective of species, age and method. To make this possible potent anaesthetics and analgesics urgently need to be licensed for use in these species. This would provide an evidence base for their use and extricate veterinary practitioners from the need to use the cascade system with its associated liabilities. Current literature has been reviewed here and possible new approaches discussed in order to establish solutions that are suitable for the animals, their keepers and veterinarians. Schattauer GmbH.

Efficacy of oral meloxicam suspension for prevention of pain and inflammation following band and surgical castration in calves.

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Olson, M E; Ralston, Brenda; Burwash, Les; Matheson-Bird, Heather; Allan, Nick D

2016-06-13

Castration is one of the most common procedures performed on beef and dairy cattle. The objective of the study was to determine the efficacy of meloxicam oral suspension in reducing pain and inflammation in calves following band or surgical castration. Two identical trials with the exception of the method of castration (Band Castration Study 1 and Surgical Castration Study 2) were conducted. Sixty (60) healthy Holstein calves 4 to 5 months of age (138-202 Kg) were used. Animals received either Meloxicam Oral Suspension at a dose of 1 mg/kg BW (n = 15 Study 1 and 15 Study 2) or Saline (n = 15 Study 1 and 15 Study 2) 2 h before castration. Physiological (Heart Rate, Plasma Cortisol and Plasma Substance P) and Behavioral (Visual Analog Scale (VAS), Accelerometers and tail Pedometers) evaluations were conducted before (day -1) and after Castration (Day 0, 1, 2, 3). Inflammation was evaluated daily by providing an individual animal score (Study1) or with a measurement of scrotal thickness (Study 2). Heart rates were significantly greater in control animals following band and surgical castration. Plasma cortisol and substance P were significantly reduced in animals receiving Meloxicam Oral Suspension. Control animals had significantly greater VAS scores. Accelerometers showed that meloxicam treated animals had a significantly greater motion index and number of steps as well as less % time lying and number of lying bouts. The scrotal inflammation (based on scrotal swelling) was significantly decreased in the meloxicam treated animals compared to the control animals on day 1, day 2 and 3. Meloxicam Oral Suspension was able to significantly reduce the display of painful behaviors and physiological responses to pain in band castrated and surgical castrated calves for up to 72 h following a single oral treatment of 1 mg/kg body weight. Meloxicam Oral Suspension was able to significantly reduce scrotal inflammation in band castrated and surgical castrated calves.

Ganho de peso e características de carcaça de bovinos Nelore castrados ou não-castrados terminados em confinamento Weight gain and characteristics of carcass of castrated or non-castrated Nellore cattle finished in confinement

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Fredson Vieira e Silva

2008-12-01

ético.The objective of this work was to evaluate weight gain and carcass characteristics Nellore cattle, castrated or non-castrated, finished in confinement. It was used Thirty six animals with 24 months old and initial 445.30 kg BW (non-castrated or 449.57 kg BW (castrated at 400 kg BW. The animals were slaughtered at 50 days of confinement, when reached 516.30 kg BW (non-castrated and 506.86 kg BW (castrated. Non-castrated animals did not have an increase in final BW, but showed higher weight gain (1.42 and 1.15 kg. Hot carcass weight (272.77 and 261.89 kg and cold carcass weight (266.13 and 258.24 kg did not differ between non-castrated and castrated animals. Non-castrated animals showed higher hot carcass yield (52.88 vs. 51.65% however, cold carcass yield was similar between groups (51.55 and 52.39%, due to smaller chilling loss in castrated animals (2.43 vs. 1.40%. Special hindquarter absolute weights (133.07 and 131.55 kg, forequarter (105.65 and 100.09 kg and spare ribs (27.41 and 26.60 kg did not differ between non-castrated and castrated animals. Forequarter relative values castrated animals were higher than the non-castrated (50.93 versus 50.00%. The striploin of non-castrated animals was heavier than that of castrated (8.41 vs. 7.90 kg. Fat thickness (2.05 vs. 2.21 mm and loin eye area (66.98 versus 67.48 cm² did not differ between non-castrated and castrated animals. Cold carcass pH in predetermined time until setting of rigor mortis is also similar between and non-castrated and castrated animals. Non-castrated and castrated animals have satisfactory carcass weight, but have not fat thickness less than 3 mm, when confined for 50 days with diet based on sugar cane and concentrate. To match the fat thickness, the diet of the animals must be balanced with higher energy level.

Temporal patterns of inflammatory gene expression in local tissues after banding or burdizzo castration in cattle

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Sweeney Torres

2009-09-01

Full Text Available Abstract Background Castration of male cattle has been shown to elicit inflammatory reactions and acute inflammation is initiated and sustained by the participation of cytokines. Methods Sixty continental × beef bulls (Mean age 12 ± (s.e. 0.2 months; Mean weight 341 ± (s.e. 3.0 kg were blocked by weight and randomly assigned to one of three treatments (n = 20 animals per treatment: 1 untreated control (Con; 2 banding castration at 0 min (Band; 3 Burdizzo castration at 0 min (Burd. Samples of the testis, epididymis and scrotal skin were collected surgically from 5 animals from each group at 12 h, 24 h, 7 d, and 14 d post-treatment, and analysed using real-time PCR. A repeated measurement analysis (Proc GLM was performed using SAS. If there was no treatment and time interaction, main effects of treatment by time were tested by ANOVA. Results Electrophoresis data showed that by 7 d post-castration RNA isolated from all the testicle samples of the Burd castrated animals, the epididymis and middle scrotum samples from Band castrates were degraded. Transitory effects were observed in the gene expression of IFN-γ, IL-6, IL-8 and TNF-α at 12 h and 24 h post treatment. Burd castrates had greater (P Conclusion Banding castration caused more inflammatory associated gene expression changes to the epididymis and scrotum than burdizzo. Burdizzo caused more severe acute inflammatory responses, in terms of pro-inflammatory cytokine gene expression, in the testis and epididymis than banding.

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

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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.

Quantitative analysis of MDR1 (multidrug resistance) gene expression in human tumors by polymerase chain reaction

International Nuclear Information System (INIS)

Noonan, K.E.; Beck, C.; Holzmayer, T.A.; Chin, J.E.; Roninson, I.B.; Wunder, J.S.; Andrulis, I.L.; Gazdar, A.F.; Willman, C.L.; Griffith, B.; Von Hoff, D.D.

1990-01-01

The resistance of tumor cells ot chemotheraprutic drugs is a major obstacle to successful cancer chemotherapy. In human cells, expression of the MDR1 gene, encoding a transmembrane efflux pump (P-glycoprotein), leads to decreased intracellular accumulation and resistance to a variety of lipophilic drugs (multidrug resistance; MDR). The levels of MDR in cell lines selected in bitro have been shown to correlate with the steady-state levels of MDR1 mRNA and P-glycoprotein. In cells with a severalfold increase in cellular drug resistance, MDR1 expression levels are close to the limits of detection by conventional assays. MDR1 expression has been frequently observed in human tumors after chemotherapy and in some but not all types of clinically refactory tumors untreated with chemotherapeutic drugs. The authors have devised a highly sensitive, specific, and quantitative protocol for measuring the levels of MDR1 mRNA in clincal samples, based on the polymerase chain reaction. They have used this assay to measure MDR1 gene expression in MDR cell lines and >300 normal tissues, tumor-derived cell lines, and clinical specimens of untreated tumors of the types in which MDR1 expression was rarely observed by standard assays. Low levels of MDR1 expression were found by polymerase chain reaction in most solid tumors and leukemias tested. The frequency of samples without detectable MDR1 expression varied among different types of tumors; MDR1-negative samples were ost common among tumor types known to be relatively responsive to chemotherapy

pH regulation in sensitive and multidrug resistant Ehrlich ascites tumor cells

DEFF Research Database (Denmark)

Litman, Thomas; Pedersen, S F; Kramhøft, B

1998-01-01

Maintenance and regulation of intracellular pH (pHi) was studied in wild-type Ehrlich ascites tumor cells (EHR2) and five progressively daunorubicin-resistant, P-glycoprotein (P-gp)-expressing strains, the maximally resistant of which is EHR2/1.3. Steady-state pHi was similar in cells expressing...

Prospective Genomic Profiling of Prostate Cancer Across Disease States Reveals Germline and Somatic Alterations That May Affect Clinical Decision Making.

Science.gov (United States)

Abida, Wassim; Armenia, Joshua; Gopalan, Anuradha; Brennan, Ryan; Walsh, Michael; Barron, David; Danila, Daniel; Rathkopf, Dana; Morris, Michael; Slovin, Susan; McLaughlin, Brigit; Curtis, Kristen; Hyman, David M; Durack, Jeremy C; Solomon, Stephen B; Arcila, Maria E; Zehir, Ahmet; Syed, Aijazuddin; Gao, Jianjiong; Chakravarty, Debyani; Vargas, Hebert Alberto; Robson, Mark E; Joseph, Vijai; Offit, Kenneth; Donoghue, Mark T A; Abeshouse, Adam A; Kundra, Ritika; Heins, Zachary J; Penson, Alexander V; Harris, Christopher; Taylor, Barry S; Ladanyi, Marc; Mandelker, Diana; Zhang, Liying; Reuter, Victor E; Kantoff, Philip W; Solit, David B; Berger, Michael F; Sawyers, Charles L; Schultz, Nikolaus; Scher, Howard I

2017-07-01

A long natural history and a predominant osseous pattern of metastatic spread are impediments to the adoption of precision medicine in patients with prostate cancer. To establish the feasibility of clinical genomic profiling in the disease, we performed targeted deep sequencing of tumor and normal DNA from patients with locoregional, metastatic non-castrate, and metastatic castration-resistant prostate cancer (CRPC). Patients consented to genomic analysis of their tumor and germline DNA. A hybridization capture-based clinical assay was employed to identify single nucleotide variations, small insertions and deletions, copy number alterations and structural rearrangements in over 300 cancer-related genes in tumors and matched normal blood. We successfully sequenced 504 tumors from 451 patients with prostate cancer. Potentially actionable alterations were identified in DNA damage repair (DDR), PI3K, and MAP kinase pathways. 27% of patients harbored a germline or a somatic alteration in a DDR gene that may predict for response to PARP inhibition. Profiling of matched tumors from individual patients revealed that somatic TP53 and BRCA2 alterations arose early in tumors from patients who eventually developed metastatic disease. In contrast, comparative analysis across disease states revealed that APC alterations were enriched in metastatic tumors, while ATM alterations were specifically enriched in CRPC. Through genomic profiling of prostate tumors representing the disease clinical spectrum, we identified a high frequency of potentially actionable alterations and possible drivers of disease initiation, metastasis and castration-resistance. Our findings support the routine use of tumor and germline DNA profiling for patients with advanced prostate cancer, for the purpose of guiding enrollment in targeted clinical trials and counseling families at increased risk of malignancy.

Low levels of PRB3 mRNA are associated with dopamine-agonist resistance and tumor recurrence in prolactinomas.

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Wang, Fei; Gao, Hua; Li, Chuzhong; Bai, Jiwei; Lu, Runchun; Cao, Lei; Wu, Yongtu; Hong, Lichuan; Wu, Yonggang; Lan, Xiaolei; Zhang, Yazhuo

2014-01-01

Prolactinomas, or prolactin-secreting adenomas, constitute the most common type of hyperfunctioning pituitary adenoma. Dopamine agonists are used as first-line medication for prolactinomas, but the tumors are resistant to the therapy in 5-18 % of patients. To explore potential mechanisms of resistance to bromocriptine (a dopamine agonist), we analyzed six responsive prolactinomas and six resistant prolactinomas by whole-exome sequencing. We identified ten genes with sequence variants that were differentially found in the two groups of tumors. The expression of these genes was then quantified by real-time reverse-transcription PCR (RT-qPCR) in the 12 prolactinomas and in six normal pituitary glands. The mRNA levels of one of the genes, PRB3, were about fourfold lower in resistant prolactinomas than in the responsive tumors (p = 0.02). Furthermore, low PRB3 expression was also associated with tumor recurrence. Our results suggest that low levels of PRB3 mRNA may have a role in dopamine-agonist resistance and tumor recurrence of prolactinomas.

Stress responses in lambs castrated with three different methods

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Paola Sandra Nicolussi

2010-01-01

Full Text Available The present work was conducted to evaluate the animal response to stress in lambs caused by three different castration techniques. Forty-six male lambs aged 4-5 months were randomly allocated to one of four groups including Burdizzo (B, scrotal ablation (SA, orchiectomy (OR and control handling (H. Local anaesthesia (lidocaine 2% was administered in both spermatic cords and the scrotal neck of lambs before each treatment. Blood samples were collected at -30, -10, +1, +20, +40, +60, +120, and +180 minutes. Serum cortisol concentrations were determined using a competitive immunoassay and the area under the curve (AUC was calculated for each lamb. The following biochemical parameters were assayed for each animal at each time point: alanine aminotransferase (ALT, aspartate aminotransferase (AST, lactate dehydrogenase (LDH, creatine kinase (CK and glucose (GLU. The time needed for total lesion resolution and weight gain of each animal was recorded. Orchiectomy elicits the greatest cortisol response, significantly greater than that seen in similarly handled controls (P≤0.01, Burdizzo and scrotal ablation groups (P≤0.05. The serum cortisol AUC was higher in the scrotal ablation group (P≤0.05 than controls, but lower than in the orchiectomy group (P≤0.05. The Burdizzo group didn’t differ from controls. Serum glucose levels of the castrated lambs differed significantly from the control group, following a trend similar to cortisol. No change was seen in ALT, AST, LDH or CK. No difference in weight gain was seen among the groups. Our results suggest that use of the Burdizzo is the preferable castration technique for adult lambs, while scrotal ablation is a valid surgical alternative to orchiectomy and permits more rapid wound healing that is ideal for extensive management where flocks are not under close observation.

Comprehensive Profiling of the Androgen Receptor in Liquid Biopsies from Castration-resistant Prostate Cancer Reveals Novel Intra-AR Structural Variation and Splice Variant Expression Patterns.

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De Laere, Bram; van Dam, Pieter-Jan; Whitington, Tom; Mayrhofer, Markus; Diaz, Emanuela Henao; Van den Eynden, Gert; Vandebroek, Jean; Del-Favero, Jurgen; Van Laere, Steven; Dirix, Luc; Grönberg, Henrik; Lindberg, Johan

2017-08-01

Expression of the androgen receptor splice variant 7 (AR-V7) is associated with poor response to second-line endocrine therapy in castration-resistant prostate cancer (CRPC). However, a large fraction of nonresponding patients are AR-V7-negative. To investigate if a comprehensive liquid biopsy-based AR profile may improve patient stratification in the context of second-line endocrine therapy. Peripheral blood was collected from patients with CRPC (n=30) before initiation of a new line of systemic therapy. We performed profiling of circulating tumour DNA via low-pass whole-genome sequencing and targeted sequencing of the entire AR gene, including introns. Targeted RNA sequencing was performed on enriched circulating tumour cell fractions to assess the expression levels of seven AR splice variants (ARVs). Somatic AR variations, including copy-number alterations, structural variations, and point mutations, were combined with ARV expression patterns and correlated to clinicopathologic parameters. Collectively, any AR perturbation, including ARV, was detected in 25/30 patients. Surprisingly, intra-AR structural variation was present in 15/30 patients, of whom 14 expressed ARVs. The majority of ARV-positive patients expressed multiple ARVs, with AR-V3 the most abundantly expressed. The presence of any ARV was associated with progression-free survival after second-line endocrine treatment (hazard ratio 4.53, 95% confidence interval 1.424-14.41; p=0.0105). Six out of 17 poor responders were AR-V7-negative, but four carried other AR perturbations. Comprehensive AR profiling, which is feasible using liquid biopsies, is necessary to increase our understanding of the mechanisms underpinning resistance to endocrine treatment. Alterations in the androgen receptor are associated with endocrine treatment outcomes. This study demonstrates that it is possible to identify different types of alterations via simple blood draws. Follow-up studies are needed to determine the effect of

15-Hydroxyprostaglandin dehydrogenase inactivation as a mechanism of resistance to celecoxib chemoprevention of colon tumors.

LENUS (Irish Health Repository)

Yan, Min

2009-06-09

Pharmacologic inhibitors of the prostaglandin-synthesizing COX-2 oncogene prevent the development of premalignant human colon adenomas. However, resistance to treatment is common. In this study, we show that the adenoma prevention activity of the COX-2 inhibitor celecoxib requires the concomitant presence of the 15-hydroxyprostaglandin dehydrogenase (15-PGDH) tumor suppressor gene, and that loss of 15-PGDH expression imparts resistance to celecoxib\\'s anti-tumor effects. We first demonstrate that the adenoma-preventive activity of celecoxib is abrogated in mice genetically lacking 15-PGDH. In FVB mice, celecoxib prevents 85% of azoxymethane-induced tumors >1 mm in size, but is essentially inactive in preventing tumor induction in 15-PGDH-null animals. Indeed, celecoxib treated 15-PGDH null animals develop more tumors than do celecoxib naive WT mice. In parallel with the loss of tumor prevention activity, celecoxib-mediated suppression of colonic PGE(2) levels is also markedly attenuated in 15-PGDH-null versus WT mice. Finally, as predicted by the murine models, humans with low colonic 15-PGDH levels also exhibit celecoxib resistance. Specifically, in a colon adenoma prevention trial, in all cases tested, individuals who developed new adenomas while receiving celecoxib treatment were also found as having low colonic 15-PGDH levels.

Transformation Resistance in a Premature Aging Disorder Identifies a Tumor-Protective Function of BRD4

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Patricia Fernandez

2014-10-01

Full Text Available Summary: Advanced age and DNA damage accumulation are prominent risk factors for cancer. The premature aging disorder Hutchinson-Gilford progeria syndrome (HGPS provides a unique opportunity for studying the interplay between DNA damage and aging-associated tumor mechanisms, given that HGPS patients do not develop tumors despite elevated levels of DNA damage. Here, we have used HGPS patient cells to identify a protective mechanism to oncogenesis. We find that HGPS cells are resistant to neoplastic transformation. Resistance is mediated by the bromodomain protein BRD4, which exhibits altered genome-wide binding patterns in transformation-resistant cells, leading to inhibition of oncogenic dedifferentiation. BRD4 also inhibits, albeit to a lower extent, the tumorigenic potential of transformed cells from healthy individuals. BRD4-mediated tumor protection is clinically relevant given that a BRD4 gene signature predicts positive clinical outcome in breast and lung cancer. Our results demonstrate a protective function for BRD4 and suggest tissue-specific roles for BRD4 in tumorigenesis. : The premature aging disorder Hutchinson-Gilford progeria syndrome (HGPS provides a unique tool for studying the interplay between DNA damage and aging-associated tumor mechanisms, given that HGPS patients do not develop tumors despite elevated levels of DNA damage. Using a genome-wide RNAi screen, Fernandez et al. now identify the bromodomain protein BRD4 as a mediator of the oncogenic resistance of HGPS cells. This tumor-protective function of BRD4 involves inhibition of oncogenic dedifferentiation and is also active in non-HGPS cells in a tissue-specific manner.

Heterogeneity in induced thermal resistance of rat tumor cell clones

International Nuclear Information System (INIS)

Tomasovic, S.P.; Rosenblatt, P.L.; Heitzman, D.

1983-01-01

Four 13762NF rat mammary adenocarcinoma clones were examined for their survival response to heating under conditions that induced transient thermal resistance (thermotolerance). Clones MTC and MTF7 were isolated from the subcutaneous locally growing tumor, whereas clones MTLn2 and MTLn3 were derived from spontaneous lung metastases. There was heterogeneity among these clones in thermotolerance induced by either fractionated 45 0 C or continuous 42 0 C heating, but the order of sensitivity was not necessarily the same. The clones developed thermal resistance at different rates and to different degrees within the same time intervals. There was heterogeneity between clones isolated from within either the primary site or metastatic lesions. However, clones derived from metastatic foci did not intrinsically acquire more or less thermotolerance to fractionated 45 0 C or continuous 42 0 C heating than did clones from the primary tumor. Further, there was no apparent relationship between any phenotypic properties that conferred more or less thermotolerance in vitro and any phenotypic properties that conferred enhanced metastatic success of these same clones by spontaneous (subcutaneous) or experimental (intravenous) routes in vivo. These tumor clones also differ in their karyotype, metastatic potential, cell surface features, sensitivity to x-irradiation and drugs, and ability to repair sublethal radiation damage. These results provide further credence to the concept that inherent heterogeneity within tumors may be as important in therapeutic success as other known modifiers of outcome such as site and treatment heterogeneity

Verapamil inhibits tumor progression of chemotherapy-resistant pancreatic cancer side population cells

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ZHAO, LU; ZHAO, YUE; SCHWARZ, BETTINA; MYSLIWIETZ, JOSEF; HARTIG, ROLAND; CAMAJ, PETER; BAO, QI; JAUCH, KARL-WALTER; GUBA, MAKUS; ELLWART, JOACHIM WALTER; NELSON, PETER JON; BRUNS, CHRISTIANE JOSEPHINE

2016-01-01

Tumor side population (SP) cells display stem-like properties that can be modulated by treatment with the calcium channel blocker verapamil. Verapamil can enhance the cytotoxic effects of chemotherapeutic drugs and multi-drug resistance by targeting the transport function of the P-glycoprotein (P-gp). This study focused on the therapeutic potential of verapamil on stem-like SP tumor cells, and further investigated its chemosensitizing effects using L3.6pl and AsPC-1 pancreatic carcinoma models. As compared to parental L3.6pl cells (0.9±0.22%), L3.6pl gemcitabine-resistant cells (L3.6plGres) showed a significantly higher percentage of SP cells (5.38±0.99%) as detected by Hoechst 33342/FACS assays. The L3.6plGres SP cells showed stable gemcitabine resistance, enhanced colony formation ability and increased tumorigenicity. Verapamil effectively inhibited L3.6plGres and AsPC-1 SP cell proliferation in vitro. A pro-apoptotic effect of verapamil was observed in L3.6pl cells, but not in L3.6plGres cells, which was linked to their differential expression of P-gp and equilibrative nucleoside transporter-1 (ENT-1). In an orthotopic pancreatic cancer mouse model, both low and high dose verapamil was shown to substantially reduce L3.6plGres-SP cell tumor growth and metastasis, enhance tumor apoptosis, and reduce microvascular density. PMID:27177126

Experience with the delegation of anaesthesia for disbudding and castration to trained and certified livestock owners.

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Alsaaod, Maher; Doherr, Marcus G; Greber, Deborah; Steiner, Adrian

2014-02-04

Anaesthesia is mandatory for disbudding and castrating calves and lambs of any age, in Switzerland. According to the "anaesthesia delegation model" (ADM), anaesthesia for disbudding calves delegation of anaesthesia for disbudding calves and procedures II and III were anaesthesia for castrating calves and lambs. Procedure I was performed with local anaesthesia in all farms of 51.8% of the veterinary practices, while this was only 39.3% and 7.6% for procedures II and III (p delegation of anaesthesia to certified farmers may be a promising model to reinforce the obligation to provide local anaesthesia for disbudding and castrating calves, but to a lesser extent for castrating lambs.

Randomized, placebo-controlled, phase III trial of sunitinib plus prednisone versus prednisone alone in progressive, metastatic, castration-resistant prostate cancer.

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Michaelson, M Dror; Oudard, Stephane; Ou, Yen-Chuan; Sengeløv, Lisa; Saad, Fred; Houede, Nadine; Ostler, Peter; Stenzl, Arnulf; Daugaard, Gedske; Jones, Robert; Laestadius, Fredrik; Ullèn, Anders; Bahl, Amit; Castellano, Daniel; Gschwend, Juergen; Maurina, Tristan; Chow Maneval, Edna; Wang, Shaw-Ling; Lechuga, Maria Jose; Paolini, Jolanda; Chen, Isan

2014-01-10

We evaluated angiogenesis-targeted sunitinib therapy in a randomized, double-blind trial of metastatic castration-resistant prostate cancer (mCRPC). Men with progressive mCRPC after docetaxel-based chemotherapy were randomly assigned 2:1 to receive sunitinib 37.5 mg/d continuously or placebo. Patients also received oral prednisone 5 mg twice daily. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS). Two interim analyses were planned. Overall, 873 patients were randomly assigned to receive sunitinib (n = 584) or placebo (n = 289). The independent data monitoring committee stopped the study for futility after the second interim analysis. After a median overall follow-up of 8.7 months, median OS was 13.1 months and 11.8 months for sunitinib and placebo, respectively (hazard ratio [HR], 0.914; 95% CI, 0.762 to 1.097; stratified log-rank test, P = .168). PFS was significantly improved in the sunitinib arm (median 5.6 v 4.1 months; HR, 0.725; 95% CI, 0.591 to 0.890; stratified log-rank test, P < .001). Toxicity and rates of discontinuations because of adverse events (AEs; 27% v 7%) were greater with sunitinib than placebo. The most common treatment-related grade 3/4 AEs were fatigue (9% v 1%), asthenia (8% v 2%), and hand-foot syndrome (7% v 0%). Frequent treatment-emergent grade 3/4 hematologic abnormalities were lymphopenia (20% v 11%), anemia (9% v 8%), and neutropenia (6% v < 1%). The addition of sunitinib to prednisone did not improve OS compared with placebo in docetaxel-refractory mCRPC. The role of antiangiogenic therapy in mCRPC remains investigational.

Effect of Surgical and Immunological Castration on Haematological ...

African Journals Online (AJOL)

olayemitoyin

Summary: Welfare concerns are growing regarding surgical castration (SC) in pets, necessitating the need for non-surgical alternatives. ..... Doctoral Thesis. Swedish ... Pharmacological advances in canine and feline reproduction. Topics in.

The effects of castration on the growth parameters, carcass yield and meat chemical composition of intensively reared Common Pheasant (Phasianus colchicus colchicus L.

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Renata Baric-Rafaj

2010-01-01

Full Text Available The effects of castration on growth performance, carcass characteristics and chemical composition of m. iliotibilais cranialis and m. pectoralis superficialis of pheasants were examined. Forty pheasants reared in commercial pheasantry were included in the experiment. Half of the pheasants were castrated at 8 weeks of age. Values for live weight tended to be higher in castrated pheasants in the 24th week (P<0.1 and values for weight gain were significantly higher between the 16th and 24th weeks (P<0.05. Feed-to-gainratio (8th – 32nd week was significantly better (P<0.05 in castrated pheasants. Eviscerated weight and dressing percentage at 32nd week were not significantly different between treatments. The chemical composition of m. iliotibilais cranialis and m. pectoralis superficialis showed significantly higher values of fat (P<0.01 and moisture (P<0.05 in castrated pheasants in comparison with intact ones. Protein content of both muscles was higher in intact pheasants (P<0.05. Body part weights were not influenced by the treatment with the exception of heart weight, which was significantly higher in the intact pheasants (P<0.05. We concluded that castration tended to improve growth performance only in the first 24 weeks of the fattening period and, therefore, continuation of fattening after that period is no longer feasible. The most important characteristic of the castrated pheasant’s meat was an increased amount of fat. More studies under different feeding and alternative breeding systems are necessary to improve production.

Fluorine-18-fluorocholine PET/CT parameters predictive for hematological toxicity to radium-223 therapy in castrate-resistant prostate cancer patients with bone metastases: a pilot study.

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Vija Racaru, Lavinia; Sinigaglia, Mathieu; Kanoun, Salim; Ben Bouallègue, Fayçal; Tal, Ilan; Brillouet, Sévérine; Bauriaud-Mallet, Mathilde; Zerdoud, Slimane; Dierickx, Lawrence; Vallot, Delphine; Caselles, Olivier; Gabiache, Erwan; Pascal, Pierre; Courbon, Frederic

2018-05-21

This study aims to predict hematological toxicity induced by Ra therapy. We investigated the value of metabolically active bone tumor volume (MBTV) and total bone lesion activity (TLA) calculated on pretreatment fluorine-18-fluorocholine (F-FCH) PET/CT in castrate-resistant prostate cancer (CRPC) patients with bone metastases treated with Ra radionuclide therapy. F-FCH PET/CT imaging was performed in 15 patients with CRPC before treatment with Ra. Bone metastatic disease was quantified on the basis of the maximum standardized uptake value (SUV), total lesion activity (TLA=MBTV×SUVmean), or MBTV/height (MBTV/H) and TLA/H. F-FCH PET/CT bone tumor burden and activity were analyzed to identify which parameters could predict hematological toxicity [on hemoglobin (Hb), platelets (PLTs), and lymphocytes] while on Ra therapy. Pearson's correlation was used to identify the correlations between age, prostate-specific antigen, and F-FCH PET parameters. MBTV ranged from 75 to 1259 cm (median: 392 cm). TLA ranged from 342 to 7198 cm (median: 1853 cm). Patients benefited from two to six cycles of Ra (n=56 cycles in total). At the end of Ra therapy, five of the 15 (33%) patients presented grade 2/3 toxicity on Hb and lymphocytes, whereas three of the 15 (20%) patients presented grade 2/3 PLT toxicity.Age was correlated negatively with both MBTV (r=-0.612, P=0.015) and TLA (r=-0.596, P=0.018). TLA, TLA/H, and MBTV/H predicted hematological toxicity on Hb, whereas TLA/H and MBTV/H predicted toxicity on PLTs at the end of Ra cycles. Receiver operating characteristic curve analysis allowed to define the cutoffs for MBTV (915 cm) and TLA (4198 cm) predictive for PLT toxicity, with an accuracy of 0.92 and 0.99. Tumor bone burden calculation is feasible with F-FCH PET/CT with freely available open-source software. In this pilot study, baseline F-FCH PET/CT markers (TLA, MBTV) have shown abilities to predict Hb and PLT toxicity after Ra therapy and could be explored for

Antiangiogenic Therapy and Mechanisms of Tumor Resistance in Malignant Glioma

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Ruman Rahman

2010-01-01

Full Text Available Despite advances in surgery, radiation therapy, and chemotherapeutics, patients with malignant glioma have a dismal prognosis. The formations of aberrant tumour vasculature and glioma cell invasion are major obstacles for effective treatment. Angiogenesis is a key event in the progression of malignant gliomas, a process involving endothelial cell proliferation, migration, reorganization of extracellular matrix and tube formation. Such processes are regulated by the homeostatic balance between proangiogenic and antiangiogenic factors, most notably vascular endothelial growth factors (VEGFs produced by glioma cells. Current strategies targeting VEGF-VEGF receptor signal transduction pathways, though effective in normalizing abnormal tumor vasculature, eventually result in tumor resistance whereby a highly infiltrative and invasive phenotype may be adopted. Here we review recent anti-angiogenic therapy for malignant glioma and highlight implantable devices and nano/microparticles as next-generation methods for chemotherapeutic delivery. Intrinsic and adaptive modes of glioma resistance to anti-angiogenic therapy will be discussed with particular focus on the glioma stem cell paradigm.

Comparative efficacy, tolerability, and survival outcomes of various radiopharmaceuticals in castration-resistant prostate cancer with bone metastasis: a meta-analysis of randomized controlled trials

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Tunio M

2015-09-01

Full Text Available Mutahir Tunio,1 Mushabbab Al Asiri,1 Abdulrehman Al Hadab,1 Yasser Bayoumi2 1Radiation Oncology, Comprehensive Cancer Center, King Fahad Medical City, Riyadh, Saudi Arabia; 2Radiation Oncology, National Cancer Institute, Cairo University, Cairo, Egypt Background: A meta-analysis was conducted to assess the impact of radiopharmaceuticals (RPs in castration-resistant prostate cancer (CRPC on pain control, symptomatic skeletal events (SSEs, toxicity profile, quality of life (QoL, and overall survival (OS.Materials and methods: The PubMed/MEDLINE, CANCERLIT, EMBASE, Cochrane Library database, and other search engines were searched to identify randomized controlled trials (RCTs comparing RPs with control (placebo or radiation therapy in metastatic CRPC. Data were extracted and assessed for the risk of bias (Cochrane’s risk of bias tool. Pooled data were expressed as odds ratio (OR, with 95% confidence intervals (CIs; Mantel–Haenszel fixed-effects model.Results: Eight RCTs with a total patient population of 1,877 patients were identified. The use of RP was associated with significant reduction in pain intensity and SSE (OR: 0.63, 95% CI: 0.51–0.78, I2=27%, P<0.0001, improved QoL (OR: 0.71, 95% CI: 0.55–0.91, I2=65%, three trials, 1,178 patients, P=0.006, and a minimal improved OS (OR: 0.84, 95% CI: 0.64–1.04, I2=47%, seven trials, 1,845 patients, P=0.11. A subgroup analysis suggested an improved OS with radium-223 (OR: 0.68, 95% CI: 0.51–0.90, one trial, 921 patients and strontium-89 (OR: 0.21, 95% CI: 0.05–0.91, one trial, 49 patients. Strontium-89 (five trials was associated with increased rates of grade 3 and 4 thrombocytopenia (OR: 4.26, 95% CI: 2.22–8.18, P=0.01, leucopenia (OR: 7.98, 95% CI: 1.82–34.95, P=0.02, pain flare (OR: 6.82, 95% CI: 3.42–13.55, P=0.04, and emesis (OR: 3.61, 95% CI: 1.76–7.40, P=0.02.Conclusion: The use of RPs was associated with significant reduction in SSEs and improved QoL, while the radium-223

Androgen deprivation therapy (castration therapy and pedophilia: What’s new

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Mauro Silvani

2015-09-01

Full Text Available Andrology is a constantly evolving discipline, embracing social problems like pedophilia and its pharmacological treatment. With regard to chemical castration, the andrologist may perform an important role as part of a team of specialists. At present, no knowledge is available regarding hormonal, chromosomal or genetic alterations involved in pedophilia. International legislation primarily aims to defend childhood, but does not provide for compulsory treatment. We reviewed international literature that, at present, only comprises a few reports on research concerning androgen deprivation. Most of these refer to the use of leuprolide acetate, rather than medroxyprogesterone and cyproterone acetate, which present a larger number of side effects. Current opinions on chemical castration for pedophilia are discordant. Some surveys confirm that therapy reduces sexual thoughts and fantasies, especially in recidivism. On the other hand, some authors report that chemical castration does not modify the pedophile’s personality. In our opinion, once existing legislation has changed, andrologists could play a significant role in the selection of patients to receive androgen deprivation therapy, due in part to their knowledge about its action and side effects.

Androgenic dependence of exophytic tumor growth in a transgenic mouse model of bladder cancer: a role for thrombospondin-1

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Yao Jorge L

2008-04-01

FPDCT allows longitudinal monitoring of exophytic tumor growth in the UPII-SV40T model of BC that bypasses need for chemical carcinogens, which confound analysis of androgen effects. Androgens increase tumor cell growth in vitro and in vivo and decrease TSP1 expression, possibly explaining the therapeutic effect of castration. This effect may, in part, explain gender differences in BC incidence and implies anti-androgenic therapies may be effective in preventing and treating BC.

Tumour cell lysate-loaded dendritic cell vaccine induces biochemical and memory immune response in castration-resistant prostate cancer patients.

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Reyes, D; Salazar, L; Espinoza, E; Pereda, C; Castellón, E; Valdevenito, R; Huidobro, C; Inés Becker, M; Lladser, A; López, M N; Salazar-Onfray, F

2013-09-17

Recently, we produced a tumour antigen-presenting cells (TAPCells) vaccine using a melanoma cell lysate, called TRIMEL, as an antigen source and an activation factor. Tumour antigen-presenting cells induced immunological responses and increased melanoma patient survival. Herein, we investigated the effect of TAPCells loaded with prostate cancer cell lysates (PCCL) as an antigen source, and TRIMEL as a dendritic cell (DC) activation factor; which were co-injected with the Concholepas concholepas haemocyanin (CCH) as an adjuvant on castration-resistant prostate cancer (CRPC) patients. The lysate mix capacity, for inducing T-cell activation, was analysed by flow cytometry and Elispot. Delayed-type hypersensitivity (DTH) reaction against PCCL, frequency of CD8(+) memory T cells (Tm) in blood and prostate-specific antigen (PSA) levels in serum were measured in treated patients. The lysate mix induced functional mature DCs that were capable of activating PCCL-specific T cells. No relevant adverse reactions were observed. Six out of 14 patients showed a significant decrease in levels of PSA. DTH(+) patients showed a prolonged PSA doubling-time after treatment. Expansion of functional central and effector CD8(+) Tm were detected. Treatment of CRPC patients with lysate-loaded TAPCells and CCH as an adjuvant is safe: generating biochemical and memory immune responses. However, the limited number of cases requires confirmation in a phase II clinical trial.

Delayed response after repeated {sup 177}Lu-PSMA-617 radioligand therapy in patients with metastatic castration resistant prostate cancer

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Rahbar, Kambiz; Schaefers, Michael [University Hospital Muenster, Department of Nuclear Medicine, Muenster (Germany); Boegeman, Martin [University Hospital Muenster, Department of Urology, Muenster (Germany); Yordanova, Anna; Essler, Markus; Ahmadzadehfar, Hojjat [University Hospital Bonn, Department of Nuclear Medicine, Bonn (Germany); Eveslage, Maria [University Hospital Muenster, Institute for Biostatistics, Muenster (Germany)

2018-02-15

Radioligand therapy (RLT) using Lutetium-177 labeled PSMA-617 (Lu-PSMA) ligand is a new therapeutic option for salvage therapy in heavily pretreated patients with metastatic castration resistant prostate cancer. The aim of this retrospective study was to analyze response in patients receiving 3 cycles of Lu-PSMA. Seventy-one patients (median age: 72 years; range 44-87) received 3 cycles of RLT with Lu-PSMA (mean administered activity: 6.016 ± 0.543 GBq) every 8 weeks. Response was evaluated using serum PSA levels and a PSA decline ≥50% was considered as biochemical response. Additionally, any PSA decline after the first cycle was evaluated for further therapy effects after the second and third cycle. A total of 213 cycles were performed in 71 patients. Data for response and adverse events were available for all patients. A PSA decline ≥50% and some PSA decline occurred in 56% and 66% of the patients. Of 30 patients with a PSA response after the first cycle, 28 remained responders and 12/41 of non-responders responded to further therapy cycles. RLT with Lu-177-PSMA-617 shows respectable response rates. In this retrospective analysis, a relevant number of patients showed a delayed response, even if they did not respond to the first cycle of the therapy. (orig.)

microRNA Biomarkers to Generate Sensitivity to Abiraterone-Resistant Prostate Cancer

Science.gov (United States)

2017-09-01

CYP17A1 inhibition with abiraterone in castration- resistant prostate cancer : induction of steroidogenesis and androgen receptor splice variants...AWARD NUMBER: W81XWH-15-1-0353 TITLE: microRNA Biomarkers to Generate Sensitivity to Abiraterone-Resistant Prostate Cancer PRINCIPAL...TITLE AND SUBTITLE microRNA Biomarkers to Generate Sensitivity to Abiraterone- Resistant Prostate Cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER

Third-line treatment and 177Lu-PSMA radioligand therapy of metastatic castration-resistant prostate cancer: a systematic review

International Nuclear Information System (INIS)

Edler von Eyben, Finn; Roviello, Giandomenico; Kiljunen, Timo; Kairemo, Kalevi; Joensuu, Timo; Uprimny, Christian; Virgolini, Irene

2018-01-01

There is a controversy as to the relative efficacy of 177 Lu prostate specific membrane antigen (PSMA) radioligand therapy (RLT) and third-line treatment for patients with metastatic castration-resistant prostate cancer (mCRPC). The aim of our systematic review was to elucidate whether 177 Lu-PSMA RLT and third-line treatment have similar effects and adverse effects (PROSPERO ID CRD42017067743). The review followed Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Searches in Pubmed and Embase selected articles up to September 2017. A search in ClinicalTrials.gov indicated ongoing studies. The meta-analysis used the random-effects model. Twelve studies including 669 patients reported 177 Lu-PSMA RLT. Overall, 43% of the patients had a maximum decline of PSA of ≥50% following treatment with 177 Lu-PSMA RLT. The treatment with 177 Lu-PSMA-617 and 177 Lu-PSMA for imaging and therapy (I and T) had mainly transient adverse effects. Sixteen studies including 1338 patients reported third-line treatment. Overall, 21% of the patients had a best decline of PSA of ≥50% following third-line treatment. After third-line treatment with enzalutamide and cabazitaxel, adverse effects caused discontinuation of treatment for 10% to 23% of the patients. 177 Lu-PSMA RLT gave a best PSA decline ≥50% more often than third-line treatment (mean 44% versus 22%, p = 0.0002, t test). 177 Lu-PSMA RLT gave objective remission more often than third-line treatment (overall 31 of 109 patients versus 43 of 275 patients, p = 0.004, χ 2 test). Median survival was longer after 177 Lu-PSMA RLT than after third-line treatment, but the difference was not statistically significant (mean 14 months versus 12 months, p = 0.32, t test). Adverse effects caused discontinuation of treatment more often for third-line treatment than for 177 Lu-PSMA RLT (22 of 66 patients versus 0 of 469 patients, p < 0.001, χ 2 test). As for patients with mCRPC, treatment with 177 Lu

Impact of oral meloxicam administration before and after band castration on feedlot performance and behavioral response in weanling beef bulls.

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Repenning, P E; Ahola, J K; Callan, R J; French, J T; Giles, R L; Bigler, B J; Coetzee, J F; Wulf, L W; Peel, R K; Whittier, J C; Fox, J T; Engle, T E

2013-10-01

Two experiments evaluated the effects of band castration and oral administration of an analgesic in association with castration on performance and behavioral and physiological responses in yearling beef bulls. In Exp. 1 Angus and Charolais-crossbred bull calves (n = 127; 309.8 ± 59.04 kg BW) and in Exp. 2 Hereford, Angus, and Hereford × Angus crossbred bulls (n = 30; 300.8 ± 4.96 kg BW) were stratified by BW and randomly assigned to 1 of 3 treatments: 1) band castration (BAND), 2) band castration with oral administration of meloxicam (BAND-MEL), and 3) sham castration (SHAM). The BAND and SHAM procedures were completed on d 0. The SHAM treatment consisted of all animal manipulations associated with band castration without band application. Meloxicam was administered on d -1, 0, and 1 (1.0, 0.5, and 0.5 mg/kg, respectively) via an oral bolus. Body weight and a subjective chute score (CS) were collected on d -1, 0, 1, 7, 14, and 21 (d 28 Exp. 1 only). In Exp. 2, jugular blood samples were collected immediately before castration and 24 h postcastration for substance P (SP) analysis. In Exp. 2, video documentation on d 0 was used to determine range of vertical head motion (DIST) on a subset of animals during treatment administration. In both experiments, ADG was similar (P ≥ 0.50) between BAND and BAND-MEL, but ADG in SHAM cattle was greater (P castrates in Exp. 1 and 2, respectively. In Exp. 1, CS did not differ (P ≥ 0.26) between BAND and BAND-MEL on any day, but castrates exhibited less desirable CS on d 1 and 28 than SHAM cattle. In Exp. 2, CS was not affected (P ≥ 0.41) by castration or the presence of meloxicam. In Exp. 2, DIST did not differ (P = 0.57) between BAND and BAND-MEL, but when pooled, castrates exhibited greater (P = 0.04) DIST than SHAM. In Exp. 2, plasma SP concentrations were similar between BAND and BAND-MEL (P = 0.81) and between castrates vs. sham cattle (P = 0.67). Results indicate no impact of meloxicam administration on performance

Effect of immunological castration management strategy on lipid oxidation and sensory characteristics of bacon stored under simulated food service conditions.

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Herrick, R T; Tavárez, M A; Harsh, B N; Mellencamp, M A; Boler, D D; Dilger, A C

2016-07-01

The objectives of this study were to determine the effect of 1) immunological castration (Improvest, a gonadotropin releasing factor analog-diphtheria toxoid conjugate) management strategy (age at slaughter and time of slaughter after second dose) and 2) sex on lipid oxidation and sensory characteristics of bacon stored under simulated food service conditions. For Objective 1, immunological castration management strategies included 24-wk-old immunologically castrated (IC) barrows 4, 6, 8, or 10 wk after the second Improvest dose (ASD); 26-wk-old IC barrows 6 wk ASD; and 28-wk-old IC barrows 8 wk ASD ( = 63). Objective 2 ( = 97) included IC barrows, physically castrated (PC) barrows, and gilts slaughtered at 24, 26, and 28 wks of age. Bellies from 2 slaughter dates were manufactured into bacon under commercial conditions. Bacon slices were laid out on parchment paper, packaged in oxygen-permeable poly-vinyl-lined boxes, and frozen (-33°C) for 1, 4, 8, or 12 wk to simulate food service conditions. At the end of each storage period, bacon was evaluated for lipid oxidation, moisture and lipid content, and sensory characteristics. Data from both objectives were analyzed using the MIXED procedure in SAS with belly as the experimental unit. For both objectives, as storage time increased, lipid oxidation of bacon increased ( 0.05). After 12 wk of frozen storage, lipid oxidation values for IC barrows, PC barrows, and gilts were still below 0.5 mg malondialdehyde/kg of meat, the threshold at which trained panelists may deem a food to be rancid. In conclusion, bacon shelf life characteristics were not altered by the immunological castration management strategy and bacon from IC barrows was similar to bacon from gilts. Therefore, bacon from IC barrows would result in shelf life and sensory quality similar to PC barrows and gilts.

Effect of Visceral Disease Site on Outcomes in Patients With Metastatic Castration-resistant Prostate Cancer Treated With Enzalutamide in the PREVAIL Trial.

Science.gov (United States)

Alumkal, Joshi J; Chowdhury, Simon; Loriot, Yohann; Sternberg, Cora N; de Bono, Johann S; Tombal, Bertrand; Carles, Joan; Flaig, Thomas W; Dorff, Tanya B; Phung, De; Forer, David; Noonberg, Sarah B; Mansbach, Hank; Beer, Tomasz M; Higano, Celestia S

2017-10-01

The Multinational Phase 3, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of Oral MDV3100 in Chemotherapy-Naive Patients With Progressive Metastatic Prostate Cancer Who Have Failed Androgen Deprivation Therapy (PREVAIL) trial was unique as it included patients with visceral disease. This analysis was designed to describe outcomes for the subgroup of men from PREVAIL with specific sites of visceral disease to help clinicians understand how these patients responded to enzalutamide prior to chemotherapy. Prespecified analyses examined the coprimary endpoints of radiographic progression-free survival (rPFS) and overall survival (OS) only. All other efficacy analyses were post hoc. The visceral subgroup was divided into liver or lung subsets. Patients with both liver and lung metastases were included in the liver subset. Of the 1717 patients in PREVAIL, 204 (12%) had visceral metastases at screening (liver only or liver/lung metastases, n = 74; lung only metastases, n = 130). In patients with liver metastases, enzalutamide was associated with an improvement in rPFS (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.22-0.90) but not OS (HR, 1.04; 95% CI, 0.57-1.87). In patients with lung metastases only, the HR for rPFS (0.14; 95% CI, 0.06-0.36) and the HR for OS (0.59; 95% CI, 0.33-1.06) favored enzalutamide over placebo. Patients with liver metastases had worse outcomes than those with lung metastases, regardless of treatment. Enzalutamide was well tolerated in patients with visceral disease. Enzalutamide is an active first-line treatment option for men with asymptomatic or mildly symptomatic chemotherapy-naive metastatic castration-resistant prostate cancer and visceral disease. Patients with lung-only disease fared better than patients with liver disease, regardless of treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

Weight gain of piglets subject to different protocols of castration

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Marcos Paulo Antunes de Lima

2014-06-01

Full Text Available ABSTRACT. Lima M.P.A., Gehrcke M.I., Laskoski F., Cristani J. & Oleskovicz N. [Weight gain of piglets subject to different protocols of castration.] Desempenho de ganho de peso de leitões após diferentes protocolos de castração. Revista Brasileira de Medicina Veterinária, 36(2:209-214, 2014. Departamento de Medicina Veterinária, Centro de Ciências Agroveterinárias, Universidade do Estado de Santa Catarina, Av. Luiz de Camões 2090, Conta Dinheiro, Lages, SC 88520-000, Brasil. E-mail: marcos_paulo@hotmail.com The aim this study was to evaluate the performance of weight gain of piglets castrated, and three methods of sedation and or local anesthesia compared with the traditional method recommended by the standards of Good Practices in Swine Production. We used 100 male pigs, seven days old, weighing 2.9 ± 0.50 kg, which were randomly divided into four groups: (BP Practice, in which the animals were castrated without anesthesia or analgesia, L (Lidocaine, which received 0.5 mL of lidocaine without epinephrine in each spermatic cord; SL (sedation/lidocaine which were sedated with tramadol 4mg.kg-1 and midazolam 1 mg.kg-1 intramuscular (IM, associated with the local block with 0.5 mL of lidocaine without epinephrine administered in each spermatic cord, and S (sedation, which received tramadol 4mg.kg-1 and midazolam 1mg.kg-1 IM. Recorded the weight of the animals at birth, the seventh day preceding the castration procedure, and 20 days old at the time of weaning. The data were evaluated by One Way ANOVA (ANOVA followed by Tukey test (P<0.05. The mean weights of animals at weaning were 6.15±0.86, 6.02±1.06, 5.96±0.19 and 5.51±1.14 and the average daily weight gain, the day of Castration at weaning was 0.23±0.05, 0.24±0.04, 0.23±0.06 and 0.19±0.05 respectively, for BP groups, L, SL and S. There were no significant differences between the values of the groups studied. The use of sedation protocols and or anesthetic to perform the

PET examination in intracranial tumor diagnosis of a cat

International Nuclear Information System (INIS)

Angyal, G.; Csepura, G.; Balkay, L.; Galuska, L.; Molnar, J.; Valastyan, I.

2008-01-01

This paper shows the significance of the Positron Emission Tomography (PET) in the veterinary medication through a case study of a cat brain tumor. A castrated male cat with bilateral mydriasis and blindness arrived at the veterinary clinic. After physical, laboratory and neurological investigations other sickness was ruled out and the inkling of the intracranial lesion had come to light. Brain tumor seemed the most likely to cause the illness because other symptoms appeared (for example: anorexia, depression) and they progrediated fast. PET examination, using 18 F-FDG isotope, was performed to confirm the possible causes of the cat's symptoms

PET examination in intracranial tumor diagnosis of a cat

Science.gov (United States)

Angyal, G.; Csepura, G.; Balkay, L.; Galuska, L.; Molnár, J.; Valastyán, I.

2008-12-01

This paper shows the significance of the Positron Emission Tomography (PET) in the veterinary medication through a case study of a cat brain tumor. A castrated male cat with bilateral mydriasis and blindness arrived at the veterinary clinic. After physical, laboratory and neurological investigations other sickness was ruled out and the inkling of the intracranial lesion had come to light. Brain tumor seemed the most likely to cause the illness because other symptoms appeared (for example: anorexia, depression) and they progrediated fast. PET examination, using 18F-FDG isotope, was performed to confirm the possible causes of the cat's symptoms

Concomitant tumor resistance: the role of tyrosine isomers in the mechanisms of metastases control.

Science.gov (United States)

Ruggiero, Raúl A; Bruzzo, Juan; Chiarella, Paula; Bustuoabad, Oscar D; Meiss, Roberto P; Pasqualini, Christiane D

2012-03-01

Concomitant tumor resistance (CR) is a phenomenon in which a tumor-bearing host is resistant to the growth of secondary tumor implants and metastasis. Although previous studies indicated that T-cell-dependent processes mediate CR in hosts bearing immunogenic small tumors, manifestations of CR induced by immunogenic and nonimmunogenic large tumors have been associated with an elusive serum factor. In a recently published study, we identified this factor as meta-tyrosine and ortho-tyrosine, 2 isomers of tyrosine that would not be present in normal proteins. In 3 different murine models of cancer that generate CR, both meta- and ortho-tyrosine inhibited tumor growth. Additionally, we showed that both isoforms of tyrosine blocked metastasis in a fourth model that does not generate CR but is sensitive to CR induced by other tumors. Mechanistic studies showed that the antitumor effects of the tyrosine isomers were mediated in part by early inhibition of the MAP/ERK pathway and inactivation of STAT3, potentially driving tumor cells into a state of dormancy in G(0)-phase. Other mechanisms, putatively involving the activation of an intra-S-phase checkpoint, would also inhibit tumor proliferation by accumulating cells in S-phase. By revealing a molecular basis for the classical phenomenon of CR, our findings may stimulate new generalized approaches to limit the development of metastases that arise after resection of primary tumors or after other stressors that may promote the escape of metastases from dormancy, an issue that is of pivotal importance to oncologists and their patients.

Improved Tumor-Specific Drug Accumulation by Polymer Therapeutics with pH-Sensitive Drug Release Overcomes Chemotherapy Resistance.

Science.gov (United States)

Heinrich, Anne-Kathrin; Lucas, Henrike; Schindler, Lucie; Chytil, Petr; Etrych, Tomáš; Mäder, Karsten; Mueller, Thomas

2016-05-01

The success of chemotherapy is limited by poor selectivity of active drugs combined with occurrence of tumor resistance. New star-like structured N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based drug delivery systems containing doxorubicin attached via a pH-sensitive hydrazone bond were designed and investigated for their ability to overcome chemotherapy resistance. These conjugates combine two strategies to achieve a high drug concentration selectively at the tumor site: (I) high accumulation by passive tumor targeting based on enhanced permeability and retention effect and (II) pH-sensitive site-specific drug release due to an acidic tumor microenvironment. Mice bearing doxorubicin-resistant xenograft tumors were treated with doxorubicin, PBS, poly HPMA (pHPMA) precursor or pHPMA-doxorubicin conjugate at different equivalent doses of 5 mg/kg bodyweight doxorubicin up to a 7-fold total dose using different treatment schedules. Intratumoral drug accumulation was analyzed by fluorescence imaging utilizing intrinsic fluorescence of doxorubicin. Free doxorubicin induced significant toxicity but hardly any tumor-inhibiting effects. Administering at least a 3-fold dose of pHPMA-doxorubicin conjugate was necessary to induce a transient response, whereas doses of about 5- to 6-fold induced strong regressions. Tumors completely disappeared in some cases. The onset of response was differential delayed depending on the tumor model, which could be ascribed to distinct characteristics of the microenvironment. Further fluorescence imaging-based analyses regarding underlying mechanisms of the delayed response revealed a related switch to a more supporting intratumoral microenvironment for effective drug release. In conclusion, the current study demonstrates that the concept of tumor site-restricted high-dose chemotherapy is able to overcome therapy resistance. Mol Cancer Ther; 15(5); 998-1007. ©2016 AACR. ©2016 American Association for Cancer Research.

Immunotherapy and Immune Evasion in Prostate Cancer

International Nuclear Information System (INIS)

Thakur, Archana; Vaishampayan, Ulka; Lum, Lawrence G.

2013-01-01

Metastatic prostate cancer remains to this day a terminal disease. Prostatectomy and radiotherapy are effective for organ-confined diseases, but treatment for locally advanced and metastatic cancer remains challenging. Although advanced prostate cancers treated with androgen deprivation therapy achieves debulking of disease, responses are transient with subsequent development of castration-resistant and metastatic disease. Since prostate cancer is typically a slowly progressing disease, use of immune-based therapies offers an advantage to target advanced tumors and to induce antitumor immunity. This review will discuss the clinical merits of various vaccines and immunotherapies in castrate resistant prostate cancer and challenges to this evolving field of immune-based therapies

Immunotherapy and Immune Evasion in Prostate Cancer

Energy Technology Data Exchange (ETDEWEB)

Thakur, Archana, E-mail: thakur@karmanos.org; Vaishampayan, Ulka [Department of Oncology, Wayne State University, Detroit, MI 48201 (United States); Lum, Lawrence G., E-mail: thakur@karmanos.org [Department of Oncology, Wayne State University, Detroit, MI 48201 (United States); Department of Medicine, Wayne State University, Detroit, MI 48201 (United States); Department of Immunology and Microbiology, Wayne State University, Detroit, MI 48201 (United States)

2013-05-24

Metastatic prostate cancer remains to this day a terminal disease. Prostatectomy and radiotherapy are effective for organ-confined diseases, but treatment for locally advanced and metastatic cancer remains challenging. Although advanced prostate cancers treated with androgen deprivation therapy achieves debulking of disease, responses are transient with subsequent development of castration-resistant and metastatic disease. Since prostate cancer is typically a slowly progressing disease, use of immune-based therapies offers an advantage to target advanced tumors and to induce antitumor immunity. This review will discuss the clinical merits of various vaccines and immunotherapies in castrate resistant prostate cancer and challenges to this evolving field of immune-based therapies.

Lower testosterone levels with luteinizing hormone-releasing hormone agonist therapy than with surgical castration: new insights attained by mass spectrometry

NARCIS (Netherlands)

van der Sluis, Tim M.; Bui, Hong N.; Meuleman, Eric J. H.; Heijboer, Annemieke C.; Hartman, Jeroen F.; van Adrichem, Nick; Boevé, Egbert; de Ronde, Willem; van Moorselaar, R. Jeroen A.; Vis, André N.

2012-01-01

Androgen deprivation therapy by bilateral orchiectomy (surgical castration) or luteinizing hormone-releasing hormone agonist therapy (medical castration) is recommended for advanced or metastatic prostate cancer. Both methods aim at reducing serum testosterone concentrations to a castrate level

Evaluation of common vaginal tunic ligation during field castration in draught colts.

Science.gov (United States)

Carmalt, J L; Shoemaker, R W; Wilson, D G

2008-09-01

The objective of this study was to determine if ligation of the common vaginal tunic could prevent or reduce the incidence of omental herniation and eventration in draught colts undergoing routine field castration. It was found that common vaginal tunic ligation, while not completely preventing omental herniation and evisceration, significantly reduced the incidence of these complications and should be considered in those males deemed at increased risk of significant post castration complications.

Animal welfare versus food quality: factors influencing organic consumers' preferences for alternatives to piglet castration without anaesthesia.

Science.gov (United States)

Heid, Astrid; Hamm, Ulrich

2013-10-01

Surgical piglet castration without pain relief has been banned in organic farming in the EU since the beginning of 2012. Alternative methods therefore need to be implemented that improve animal welfare and solve the underlying problem of boar taint. This paper explores German organic consumers' preferences for piglet castration without pain relief and three alternative methods. In an innovative approach using a multi-criteria decision making procedure, qualitative data from focus group discussions were compared with quantitative results from Vickrey auctions. Overall, participants preferred all alternatives to castration without pain relief. Different aspects influenced willingness-to-pay for the methods. Animal welfare was important for the evaluation of castration without pain relief and castration with anaesthesia. Food safety played a major role for willingness-to-pay for immunocastration, while taste and, to some extent, animal welfare were dominant factors for fattening of boars. These differences should be considered when communicating the alternatives. Copyright © 2013 Elsevier Ltd. All rights reserved.

Quantitative estimation of the cost of parasitic castration in a Helisoma anceps population using a matrix population model.

Science.gov (United States)

Negovetich, N J; Esch, G W

2008-10-01

Larval trematodes frequently castrate their snail intermediate hosts. When castrated, the snails do not contribute offspring to the population, yet they persist and compete with the uninfected individuals for the available food resources. Parasitic castration should reduce the population growth rate lambda, but the magnitude of this decrease is unknown. The present study attempted to quantify the cost of parasitic castration at the level of the population by mathematically modeling the population of the planorbid snail Helisoma anceps in Charlie's Pond, North Carolina. Analysis of the model identified the life-history trait that most affects lambda, and the degree to which parasitic castration can lower lambda. A period matrix product model was constructed with estimates of fecundity, survival, growth rates, and infection probabilities calculated in a previous study. Elasticity analysis was performed by increasing the values of the life-history traits by 10% and recording the percentage change in lambda. Parasitic castration resulted in a 40% decrease in lambda of H. anceps. Analysis of the model suggests that decreasing the size at maturity was more effective at reducing the cost of castration than increasing survival or growth rates of the snails. The current matrix model was the first to mathematically describe a snail population, and the predictions of the model are in agreement with published research.

Effect of a topical anaesthetic formulation on the cortisol response to surgical castration of unweaned beef calves.

Science.gov (United States)

McCarthy, D; Lomax, S; Windsor, P A; White, P J

2016-01-01

Impracticality and cost of existing pain management strategies during surgical castration of beef cattle have limited their widespread implementation on-farm. A farmer-applied topical anaesthetic formulation, originally developed and used commercially to mitigate the pain of mulesing in lambs, was investigated for its potential use for managing pain in surgically castrated calves. This formulation contained lidocaine, bupivacaine, adrenalin and cetrimide. In this study, 24 Angus bull calves were randomly allocated to (1) surgical castration (C, n=8), (2) surgical castration with the post-operative application of topical anaesthetic (CTA, n=8) and (3) sham castration/control (CON, n=8). The experiment was conducted over 2 days, with treatment groups evenly represented across each day. Calves were habituated to handling before the experiment and blood samples were collected for plasma cortisol measurement at defined time periods before, at and post treatment, (at -0.5, 0 h, then +0.5, 1, 1.5, 2, 4 and 6 h). There was a significant effect of time on cortisol concentrations across all treatment groups (Pcastration did not significantly reduce plasma cortisol concentrations. However, the trend for CTA calves to display lower cortisol concentrations than C calves warrants further investigation into the use of TA for pain relief of surgically castrated beef calves.

Expression of EGFR Under Tumor Hypoxia: Identification of a Subpopulation of Tumor Cells Responsible for Aggressiveness and Treatment Resistance

Energy Technology Data Exchange (ETDEWEB)

Hoogsteen, Ilse J., E-mail: i.hoogsteen@rther.umcn.nl [Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, Nijmegen (Netherlands); Marres, Henri A.M.; Hoogen, Franciscus J.A. van den [Department of Otorhinolaryngology/Head-Neck Surgery, Radboud University Nijmegen Medical Centre, Nijmegen (Netherlands); Rijken, Paul F.J.W.; Lok, Jasper; Bussink, Johan; Kaanders, Johannes H.A.M. [Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, Nijmegen (Netherlands)

2012-11-01

Purpose: Overexpression of epidermal growth factor receptor (EGFR) and tumor hypoxia have been shown to correlate with worse outcome in several types of cancer including head-and-neck squamous cell carcinoma. Little is known about the combination and possible interactions between the two phenomena. Methods and Materials: In this study, 45 cases of histologically confirmed squamous cell carcinomas of the head and neck were analyzed. All patients received intravenous infusions of the exogenous hypoxia marker pimonidazole prior to biopsy. Presence of EGFR, pimonidazole binding, and colocalization between EGFR and tumor hypoxia were examined using immunohistochemistry. Results: Of all biopsies examined, respectively, 91% and 60% demonstrated EGFR- and pimonidazole-positive areas. A weak but significant association was found between the hypoxic fractions of pimonidazole (HFpimo) and EGFR fractions (F-EGFR) and between F-EGFR and relative vascular area. Various degrees of colocalization between hypoxia and EGFR were found, increasing with distance from the vasculature. A high fraction of EGFR was correlated with better disease-free and metastasis-free survival, whereas a high degree of colocalization correlated with poor outcome. Conclusions: Colocalization of hypoxia and EGFR was demonstrated in head-and-neck squamous cell carcinomas, predominantly at longer distances from vessels. A large amount of colocalization was associated with poor outcome, which points to a survival advantage of hypoxic cells that are also able to express EGFR. This subpopulation of tumor cells might be indicative of tumor aggressiveness and be partly responsible for treatment resistance.

Post hoc analysis of Japanese patients from the placebo-controlled PREVAIL trial of enzalutamide in patients with chemotherapy-naive, metastatic castration-resistant prostate cancer—updated results

Science.gov (United States)

Ueda, Takeshi

2017-01-01

Abstract A post hoc analysis of interim results from PREVAIL, a Phase III, double-blind, placebo-controlled trial of men with metastatic castration-resistant prostate cancer, demonstrated that the treatment effects, safety and pharmacokinetics of enzalutamide in Japanese patients were generally consistent with those of the overall population. A recent longer term analysis of PREVAIL demonstrated continued benefit of enzalutamide treatment over placebo. Here, we report results from a post hoc analysis of Japanese patients enrolled in PREVAIL at the prespecified number of deaths for the final analysis. In Japanese patients, enzalutamide reduced the risk of death by 35% (hazard ratio, 0.65; 95% confidence interval, 0.28–1.51) and the risk of investigator-assessed radiographic progression or death by 60% (hazard ratio, 0.40; 95% confidence interval, 0.18–0.90). These results show that treatment effects and safety in Japanese patients in the final analysis of PREVAIL continued to be generally consistent with those of the overall population. PMID:28003320

Peculiarities of antioxidant system and iron metabolism in organism during development of tumor resistance to cisplatin.

Science.gov (United States)

Chekhun, V F; Lozovska, Y V; Burlaka, A P; Lukyanova, N Y; Todor, I N; Naleskina, L A

2014-09-01

To study in vivo the peculiarities of changes of iron metabolism and antioxidant system in dynamics of growth of Guerin carcinoma with different sensitivity to cisplatin. In order to evaluate the content of metallothionein-1 (MT-1) in tumor homogenates and blood serum of rats with cisplatin-sensitive and cisplatin-resistant Guerin carcinoma the immunoenzyme method was used. The evaluation of ceruloplasmin activity, content of "free iron" complexes, superoxide and NO-generating acti-vity of NADPH-oxidase and iNOS activity in neutrophils, blood serum and tumor homogenates was measured by EPR-spectro-scopy. Maximal accumulation of MT-1 in blood serum and tumor, more pronounced in resistant strain, at the border of latent and exponential phase of growth has been shown that is the evidence of protective role of this protein in the respect to the generation of free radical compounds. It has been determined that in animals with cisplatin-resistant strain of Guerin carcinoma, increase of "free iron" complexes is more apparent both on the level of tumor and organism on the background on increase of CP/TR ratio that is the consequence of organism antioxidant protection system disorder. Mentioned changes in metabolism of iron with its accumulation in tumor and further reprogramming of mitochondria metabolism and activity of NADPH-oxidase for non-transformed cells are favorable conditions for the formation of oxidative phenotype of tumor.

Temporal patterns of inflammatory gene expression in local tissues after banding or burdizzo castration in cattle

OpenAIRE

Sweeney Torres; Earley Bernadette; Pang Wanyong; Gath Vivian; Crowe Mark A

2009-01-01

Abstract Background Castration of male cattle has been shown to elicit inflammatory reactions and acute inflammation is initiated and sustained by the participation of cytokines. Methods Sixty continental × beef bulls (Mean age 12 ± (s.e.) 0.2 months; Mean weight 341 ± (s.e.) 3.0 kg) were blocked by weight and randomly assigned to one of three treatments (n = 20 animals per treatment): 1) untreated control (Con); 2) banding castration at 0 min (Band); 3) Burdizzo castration at 0 min (Burd). S...

Effect of subcutaneous Meloxicam on indicators of acute pain and distress after castration and branding in 2 mo old beef calves.

Science.gov (United States)

Meléndez, D M; Marti, S; Pajor, E A; Moya, D; Gellatly, D; Janzen, E D; Schwartzkopf-Genswein, K S

2018-06-15

The aim of this study was to assess knife castration and knife castration + branding in 2-mo old calves, and the effect of a single dose of s.c. meloxicam at mitigating pain indicators. Seventy-one Angus crossbred bull calves (128 ± 18.5 kg of BW) were used in a 3 × 2 factorial design where main factors included procedure: sham (control calves, CT; n = 23), knife (KN; n = 24) or knife + branding (BK; n = 24) and medication: single s.c. administration of lactated ringer solution (NM; n = 35) or a single dose of 0.5 mg/kg of s.c. meloxicam (M; n = 36). Physiological samples were collected at T0, 60, 90, 120 and 180 min and on d 1, 2, 3 and 7 after procedure, while behavioral observations were evaluated at 2 to 4 h and 1, 2, 3 and 7 days after procedure. A procedure × time effect (P 0.10) were observed for salivary cortisol, substance P and scrotal temperature min after the procedure or for cortisol, substance P, serum amyloid A, stride length or behavioral observations on d after the procedure. Overall, BK calves presented greater physiological and behavioral indicators of acute pain than KN calves, suggesting that the combination of knife castration + branding was more painful. Meloxicam administered s.c. was effective at reducing physiological and behavioral indicators of acute pain associated with knife castration and knife castration + branding.

Protein and Amino Acid Profile of Filial Etawah Crossbred and Castrated Filial Boer Crossbred Goat Meat

Directory of Open Access Journals (Sweden)

Hari Purnomo

2012-03-01

Full Text Available The aim of this study was to know the protein content and amino acid profile of filial Etawah and castrated Boer goat meat. The results were expected to be used as information about protein content and amino acid composition of filial Etawah and filial castrated Boer goat meat and  as a reference for further experiment about different livestock. The material of the research were loin meat, front  and back thigh of filial Etawah and filial castrated Boer goat meat. Data were analysed with t-test. The results showed that castrated filial Boer goat meat had significantly higher protein content  and 7 essensial amino acids namely lysine, leucine, arginine, phenylalanine, isoleucine, valine and histidine compared to the one from filial Etawah goat meat. Key words: protein, amino acid profiles, goat  meat

The PREVAIL Study

DEFF Research Database (Denmark)

Evans, Christopher P; Higano, Celestia S; Keane, Thomas

2016-01-01

BACKGROUND: Enzalutamide, an oral androgen receptor inhibitor, significantly improved overall survival (OS) and radiographic progression-free survival (rPFS) versus placebo in the PREVAIL trial of men with chemotherapy-naïve metastatic castration-resistant prostate cancer. OBJECTIVE: To assess...... in men with chemotherapy-naïve metastatic castration-resistant prostate cancer, with or without visceral disease, low- or high-volume bone disease, or lymph node only disease. PATIENT SUMMARY: Patients with metastatic castration-resistant prostate cancer-including those with or without visceral disease...

[Regression and therapy-resistance of primary liver tumors and liver metastases after regional chemotherapy and local tumor ablation].

Science.gov (United States)

Fischer, H-P

2005-05-01

High dosage regional chemotherapy, chemoembolization and other methods of regional treatment are commonly used to treat unresectable primary liver malignancies and liver metastases. In liver malignancies of childhood neoadjuvant chemotherapy is successfully combined with surgical treatment. Chemotherapy and local tumor ablation lead to characteristic histomorphologic changes: Complete destruction of the tumor tissue and its vascular bed is followed by encapsulated necroses. After selective eradication of the tumor cells under preservation of the fibrovasular bed the tumor is replaced by hypocellular edematous and fibrotic tissue. If completely damaged tumor tissue is absorbed quickly, the tumor area is replaced by regenerating liver tissue. Obliterating fibrohyalinosis of tumor vessels, and perivascular edema or necrosis indicate tissue damage along the vascular bed. Degenerative pleomorphism of tumor cells, steatosis, hydropic swelling and Malloryhyalin in HCC can represent cytologic findings of cytotoxic cellular damage. Macroscopic type of HCC influences significantly the response to treatment. Multinodular HCC often contain viable tumor nodules close to destroyed nodules after treatment. Encapsulated uninodular tumors undergo complete necrosis much easier. Large size and a tumor capsule limitate the effect of percutaneous injection of ethanol into HCC. In carcinomas with an infiltrating border, especially in metastases of adenocarcinomas and hepatic cholangiocarcinoma cytostatic treatment damages the tumor tissue mainly in the periphery. Nevertheless the infiltrating rim, portal veins, lymphatic spaces and bile ducts as well as the angle between liver capsule, tumor nodule and bordering parenchyma are the main refugees of viable tumor tissue even after high dosage regional chemotherapy. This local resistance is caused by special local conditions of vascularization and perfusion. These residues are the source of local tumor progression and distant metastases

Vitamin K2, a menaquinone present in dairy products targets castration-resistant prostate cancer cell-line by activating apoptosis signaling.

Science.gov (United States)

Dasari, Subramanyam; Samy, Angela Lincy Prem Antony; Kajdacsy-Balla, Andre; Bosland, Maarten C; Munirathinam, Gnanasekar

2018-05-01

The aim of this study was to evaluate the therapeutic effects of vitamin K2 (VK2) on castration-resistant prostate cancer (CRPC) and its anti-cancer mechanisms in a pre-clinical study using a VCaP cell line (ATCC ® CRL-2876™) which was established from a vertebral bone metastasis from a patient with hormone refractory prostate cancer. Our data showed that VK2 significantly inhibited CRPC VCaP cell proliferation in a dose-dependent manner at 48 h treatment in vitro. In addition, VK2 reduced the migration potential of VCaP cells and inhibited anchorage-independent growth of these cells. Our results also showed that VK2 induces apoptosis in VCaP cells. Furthermore, VK2 enforced growth arrest in VCaP cells by activating cellular senescence. Notably, VK2 treatment elevated the levels of reactive oxygen species in VCaP cells. Western blot analysis revealed that VK2 downregulated the expression of androgen receptor, BiP, survivin, while activating caspase-3 and -7, PARP-1 cleavage, p21 and DNA damage response marker, phospho-H2AX in VCaP cells. In conclusion, our study suggests that VK2 might be a potential anti-cancer agent for CRPC by specifically targeting key anti-apoptotic, cell cycle progression and metastasis-promoting signaling molecules. Copyright © 2018 Elsevier Ltd. All rights reserved.

CX4945 suppresses the growth of castration-resistant prostate cancer cells by reducing AR-V7 expression.

Science.gov (United States)

Deng, Chuangzhong; Chen, Jieping; Guo, Shengjie; Wang, Yanjun; Zhou, Qianghua; Li, Zaishang; Yang, Xingping; Yu, Xingsu; Zhang, Zhenfeng; Zhou, Fangjian; Han, Hui; Yao, Kai

2017-08-01

The aberrant expression of casein kinase 2 (CK2) has been reported to be involved in the tumorigenesis and progression of prostate cancer. The inhibition of CK2 activity represses androgen-dependent prostate cancer cells by attenuating the androgen receptor (AR) signaling pathway. In this study, we examined the effect of CK2 inhibition in castration-resistant prostate cancer (CRPC) cells, in which AR variants (ARVs) play a predominant role. A newly synthetic CK2 selective inhibitor CX4945 was utilized to study the effect of CK2 inhibition in CRPC cells by CCK8 assay and colony formation assay. Protein and mRNA levels of full-length AR (AR-FL) and AR-V7 were determined by qPCR and western blot, respectively. The nuclear translocation of p50 and p65 was assessed to reflect the activity of the NF-κB pathway. CX4945 reduced the proliferation of CRPC cells in a dose-dependent and time-dependent manner. AR-V7 rather than AR-FL was downregulated by CX4945 in both the mRNA and protein level. Furthermore, CX4945 could restore the sensitivity of CRPC cells to bicalutamide. The analysis of possible mechanisms demonstrated that the inhibition of CK2 diminished the phosphorylation of p65 at ser529 and thus attenuated the activity of the NF-κB pathway. The inhibition of CK2 by CX4945 can repress the viability of CRPC cells and restore their sensitivity to anti-androgen therapy by suppressing AR-V7. This finding presents a potential option for the treatment of prostate cancer, especially CRPC.

Celecoxib decreases growth and angiogenesis and promotes apoptosis in a tumor cell line resistant to chemotherapy

Directory of Open Access Journals (Sweden)

Carlos Rosas

2014-01-01

Full Text Available BACKGROUND: During the last few years it has been shown in several laboratories that Celecoxib (Cx, a non-steroidal anti-inflammatory agent (NSAID normally used for pain and arthritis, mediates antitumor and antiangiogenic effects. However, the effects of this drug on a tumor cell line resistant to chemotherapeutical drugs used in cancer have not been described. Herein we evaluate the angiogenic and antitumor effects of Cx in the development of a drug-resistant mammary adenocarcinoma tumor (TA3-MTXR. RESULTS: Cx reduces angiogenesis in the chick embryonic chorioallantoic membrane assay (CAM, inhibits the growth and microvascular density of the murine TA3-MTXR tumor, reduces microvascular density of tumor metastases, promotes apoptosis and reduces vascular endothelial growth factor (VEGF production and cell proliferation in the tumor. CONCLUSION: The antiangiogenic and antitumor Cx effects correlate with its activity on other tumor cell lines, suggesting that Prostaglandins (PGs and VEGF production are involved. These results open the possibility of using Celecoxib combined with other experimental therapies, ideally aiming to get synergic effects.

Downregulation of taurine uptake in multidrug resistant Ehrlich ascites tumor cells

DEFF Research Database (Denmark)

Poulsen, K A; Litman, Thomas; Eriksen, J

2002-01-01

In daunorubicin resistant Ehrlich ascites tumor cells (DNR), the initial taurine uptake was reduced by 56% as compared to the parental, drug sensitive Ehrlich cells. Kinetic experiments indicated that taurine uptake in Ehrlich cells occurs via both high- and low-affinity transporters. The maximal...... rate constant for the initial taurine uptake was reduced by 45% (high-affinity system) and 49% (low affinity system) in the resistant subline whereas the affinity of the transporters to taurine was unchanged. By immunoblotting we identified 3 TauT protein bands in the 50-70 kDa region. A visible...... reduction in the intensity of the band with the lowest molecular weight was observed in resistant cells. Quantitative RT-PCR indicated a significant reduction in the amount of taurine transporter mRNA in the resistant cells. Drug resistance in DNR Ehrlich cells is associated with overexpression of the mdr1...

Plasmonic Nanobubbles Rapidly Detect and Destroy Drug-Resistant Tumors

Science.gov (United States)

Lukianova-Hleb, Ekaterina Y.; Ren, Xiaoyang; Townley, Debra; Wu, Xiangwei; Kupferman, Michael E.; Lapotko, Dmitri O.

2012-01-01

The resistance of residual cancer cells after oncological resection to adjuvant chemoradiotherapies results in both high recurrence rates and high non-specific tissue toxicity, thus preventing the successful treatment of such cancers as head and neck squamous cell carcinoma (HNSCC). The patients' survival rate and quality of life therefore depend upon the efficacy, selectivity and low non-specific toxicity of the adjuvant treatment. We report a novel, theranostic in vivo technology that unites both the acoustic diagnostics and guided intracellular delivery of anti-tumor drug (liposome-encapsulated doxorubicin, Doxil) in one rapid process, namely a pulsed laser-activated plasmonic nanobubble (PNB). HNSCC-bearing mice were treated with gold nanoparticle conjugates, Doxil, and single near-infrared laser pulses of low energy. Tumor-specific clusters of gold nanoparticles (solid gold spheres) converted the optical pulses into localized PNBs. The acoustic signals of the PNB detected the tumor with high specificity and sensitivity. The mechanical impact of the PNB, co-localized with Doxil liposomes, selectively ejected the drug into the cytoplasm of cancer cells. Cancer cell-specific generation of PNBs and their intracellular co-localization with Doxil improved the in vivo therapeutic efficacy from 5-7% for administration of only Doxil or PNBs alone to 90% thus demonstrating the synergistic therapeutic effect of the PNB-based intracellular drug release. This mechanism also reduced the non-specific toxicity of Doxil below a detectable level and the treatment time to less than one minute. Thus PNBs combine highly sensitive diagnosis, overcome drug resistance and minimize non-specific toxicity in a single rapid theranostic procedure for intra-operative treatment. PMID:23139725

Third-line treatment and {sup 177}Lu-PSMA radioligand therapy of metastatic castration-resistant prostate cancer: a systematic review

Energy Technology Data Exchange (ETDEWEB)

Edler von Eyben, Finn [Center of Tobacco Control Research, Odense (Denmark); Roviello, Giandomenico [San Donato Hospital, Department of Oncology, Medical Oncology Unit, Arezzo (Italy); University of Trieste, Department Medical, Surgery, and Health Sciences, Trieste (Italy); Kiljunen, Timo; Kairemo, Kalevi; Joensuu, Timo [Docrates Cancer Center, Helsinki (Finland); Uprimny, Christian; Virgolini, Irene [University Hospital Innsbruck, Department of Nuclear Medicine, Innsbruck (Austria)

2018-03-15

There is a controversy as to the relative efficacy of {sup 177}Lu prostate specific membrane antigen (PSMA) radioligand therapy (RLT) and third-line treatment for patients with metastatic castration-resistant prostate cancer (mCRPC). The aim of our systematic review was to elucidate whether {sup 177}Lu-PSMA RLT and third-line treatment have similar effects and adverse effects (PROSPERO ID CRD42017067743). The review followed Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Searches in Pubmed and Embase selected articles up to September 2017. A search in ClinicalTrials.gov indicated ongoing studies. The meta-analysis used the random-effects model. Twelve studies including 669 patients reported {sup 177}Lu-PSMA RLT. Overall, 43% of the patients had a maximum decline of PSA of ≥50% following treatment with {sup 177}Lu-PSMA RLT. The treatment with {sup 177}Lu-PSMA-617 and {sup 177}Lu-PSMA for imaging and therapy (I and T) had mainly transient adverse effects. Sixteen studies including 1338 patients reported third-line treatment. Overall, 21% of the patients had a best decline of PSA of ≥50% following third-line treatment. After third-line treatment with enzalutamide and cabazitaxel, adverse effects caused discontinuation of treatment for 10% to 23% of the patients. {sup 177}Lu-PSMA RLT gave a best PSA decline ≥50% more often than third-line treatment (mean 44% versus 22%, p = 0.0002, t test). {sup 177}Lu-PSMA RLT gave objective remission more often than third-line treatment (overall 31 of 109 patients versus 43 of 275 patients, p = 0.004, χ{sup 2} test). Median survival was longer after {sup 177}Lu-PSMA RLT than after third-line treatment, but the difference was not statistically significant (mean 14 months versus 12 months, p = 0.32, t test). Adverse effects caused discontinuation of treatment more often for third-line treatment than for {sup 177}Lu-PSMA RLT (22 of 66 patients versus 0 of 469 patients, p < 0.001, χ{sup 2

Objective Measures for the Assessment of Post-Operative Pain in Bos indicus Bull Calves Following Castration

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Musk, Gabrielle C.; Hyndman, Timothy H.; Lehmann, Heidi S.; Tuke, S. Jonathon; Collins, Teresa; Johnson, Craig B.

2017-01-01

Simple Summary Surgical castration of cattle is a common husbandry procedure, and although this procedure is known to cause pain in cattle and other species, in some countries it is often performed without anaesthesia or analgesia. Society is increasingly aware of this animal welfare issue and it is creating pressure to drive research into animal welfare science with the aim of identifying practical and economical approaches to pain management in livestock. To effectively manage pain, a pain assessment must be performed. Pain assessment methods are often subjective and therefore influenced by the observer. Ideally, objective assessments that generate consistent and repeatable results between observers should be identified. Bos indicus bull calves were divided into four groups: no castration (NC, n = 6); castration with pre-operative local anaesthetic (CL n = 12); castration with pre-operative anti-inflammatory medication (CM, n = 12); and, castration without pain relief (C, n = 12). A range of objective assessments was performed: bodyweight measurements, activity, and rest levels, and four different compounds in the blood. The results of this study suggest that animals rest for longer periods after the pre-operative administration of anti-inflammatory medication. The other objective assessments measured in this study were not able to consistently differentiate between treatment groups. These findings emphasise the need for alternative quantifiable and objective indicators of pain in Bos indicus bull calves. Abstract The aim of the study was to assess pain in Bos indicus bull calves following surgical castration. Forty-two animals were randomised to four groups: no castration (NC, n = 6); castration with pre-operative lidocaine (CL, n = 12); castration with pre-operative meloxicam (CM, n = 12); and, castration alone (C, n = 12). Bodyweight was measured regularly and pedometers provided data on activity and rest from day −7 (7 days prior to surgery) to 13. Blood

Effect of surgical castration with or without oral meloxicam on the acute inflammatory response in yearling beef bulls.

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Roberts, S L; Hughes, H D; Burdick Sanchez, N C; Carroll, J A; Powell, J G; Hubbell, D S; Richeson, J T

2015-08-01

Pain management and welfare are increasingly prevalent concerns within animal agriculture. Analgesics may alleviate pain and inflammation associated with castration of beef cattle. This study was conducted to elucidate the effects of surgical castration on the acute inflammatory response and immunomodulation and whether concurrent oral administration of meloxicam (1 mg/kg BW) would alter these responses. On d -1, crossbred bull calves ( = 30; initial BW = 227.4 ± 10.3 kg) were fitted with indwelling jugular catheters and rectal temperature (RT) recording devices, placed into individual stanchions, and randomly assigned to 1 of 3 treatments. Treatment application occurred at h 0 and consisted of 1) intact bull calves treated with sham castration (CON), 2) bulls surgically castrated without meloxicam administration (CAS), and 3) bulls surgically castrated with oral meloxicam (1 mg/kg BW) administration (MEL). Blood samples were collected at 0.5-h intervals from h -2 to 4, 1.0-h intervals from h 4 to 8, and 12-h intervals from h 12 to 72. Serum was analyzed for cortisol and haptoglobin (Hp) concentrations using ELISA. Whole blood was analyzed for complete blood counts at -2, 0, 2, 4, 6, 8, 12, 24, 36, 48, 60, and 72 h, and RT was recorded in 5-min intervals. Postcastration RT was greatest for MEL (39.04), intermediate for CAS (38.99), and least for CON (38.93°C; ≤ 0.01). Serum cortisol was increased ( castration reduced the acute inflammatory response in castrates, as evidenced by a reduction in Hp and certain leukocyte concentrations; it also caused a delayed increase in RT. Further research is needed to determine if this reduced acute inflammatory response would equate to improved health and/or performance after castration.

Identification of Different Classes of Luminal Progenitor Cells within Prostate Tumors

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Supreet Agarwal

2015-12-01

Full Text Available Primary prostate cancer almost always has a luminal phenotype. However, little is known about the stem/progenitor properties of transformed cells within tumors. Using the aggressive Pten/Tp53-null mouse model of prostate cancer, we show that two classes of luminal progenitors exist within a tumor. Not only did tumors contain previously described multipotent progenitors, but also a major population of committed luminal progenitors. Luminal cells, sorted directly from tumors or grown as organoids, initiated tumors of adenocarcinoma or multilineage histological phenotypes, which is consistent with luminal and multipotent differentiation potentials, respectively. Moreover, using organoids we show that the ability of luminal-committed progenitors to self-renew is a tumor-specific property, absent in benign luminal cells. Finally, a significant fraction of luminal progenitors survived in vivo castration. In all, these data reveal two luminal tumor populations with different stem/progenitor cell capacities, providing insight into prostate cancer cells that initiate tumors and can influence treatment response.

Effect of castration age on slaughtering performance of Piemontese male cattle

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C. Lazzaroni

2010-01-01

Full Text Available Calves castration represents an old and traditional practice to obtain animal work force, but for technical, economic and social reasons in the last half of the 20th century it was left. The recent renewal of Piemontese steers rearing in the breed’s native diffusion area, for quality meat production (Biagini et al., 2001, has been spurred also for the interest in local typical dishes. Traditionally, in Piedmont calves were castrated before puberty (about 6 month of age, but now also later (12-14 month of age to benefit by the bull higher growing rate.

Complete androgen blockade safely allows for delay of cytotoxic chemotherapy in castration refractory prostate cancer

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Rafael A. Kaliks

2010-06-01

Full Text Available PURPOSE: Complete androgen blockade (CAB does not prolong overall survival (OS in patients with castration refractory prostate cancer (CRPC. Although there is variable clinical benefit with second-line hormone manipulation, we do not know which patients might benefit the most. OBJECTIVES: To identify clinical predictors of benefit of complete androgen blockade. MATERIALS AND METHODS: We reviewed the records for 54 patients who received treatment with CAB in the setting of disease progression despite castration. We evaluated progression-free survival (PFS and OS according to PSA at diagnosis, Gleason scores, age, testosterone level, and duration of prior disease control during castration in first line treatment. RESULTS: Among 54 patients who received CAB, the median PFS was 9 months (CI 4.3-13.7 and OS was 36 months (CI 24-48. We did not find an effect of PSA at diagnosis (p = 0.32, Gleason score (p = 0.91, age (p = 0.69 or disease control during castration (p = 0.87 on PFS or OS. Thirty-four patients subsequently received chemotherapy, with a mean OS of 21 months (CI 16.4-25.5, median not reached. CONCLUSION: Age, Gleason score, PSA at diagnosis and length of disease control with castration did not affect PFS or OS. In the absence of predictors of benefit, CAB should still be considered in CRPC.

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.

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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

Optimum Drug Combinations for the Sedation of Growing Boars Prior to Castration

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Lehmann, Heidi S.; Blache, Dominique; Drynan, Eleanor; Tshewang, Pema; Blignaut, David J. C.; Musk, Gabrielle C.

2017-01-01

Simple Summary Pigs are notoriously challenging patients. They are difficult to handle so the use of predictable and safe sedation techniques is required for husbandry and surgical procedures. Various combinations of sedative and analgesic drugs have been previously investigated in this species, though the combination of midazolam and detomidine with either butorphanol or morphine has not been reported for sedation in pigs. The use of these combinations was investigated in the context of adequate sedation to allow castration of boars with the aid of local anaesthetic infiltration. The combination of midazolam, detomidine with butorphanol provided a more reliable sedation combination than that including morphine. It is proposed that this combination of drugs would be useful for sedation during painful husbandry procedures in pigs. Abstract Juvenile male pigs were sedated for castration. Eight five-month old boars were sedated twice (two weeks apart) with a combination of detomidine (0.1 mg/kg), midazolam (0.2 mg/kg) and either butorphanol (0.2 mg/kg) (Group MDB, n = 8) or morphine (0.2 mg/kg) (Group MDM, n = 8) intramuscularly. The boars were positioned in lateral recumbency and lidocaine (200 mg total) was injected into the testicle and scrotal skin. Castration of a single testicle was performed on two occasions. Sedation and reaction (to positioning and surgery) scores, pulse rate, respiratory rate, haemoglobin oxygen saturation, body temperature, arterial blood gas parameters and the times to immobility and then recovery were recorded. Atipamezole was administered if spontaneous recovery was not evident within 60 min of sedative administration. Data were compared with either a paired-sample t-test or a Wilcoxon-Signed Rank Test. There was no difference in sedation score, body temperature, respiratory rate and haemoglobin oxygen saturation between MDB and MDM. Mild hypoxaemia was noted in both groups. There was less reaction to castration after MDB. The pulse rate

Enhancement of anticancer effect of interferon-γ gene transfer against interferon-γ-resistant tumor by depletion of tumor-associated macrophages.

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Kiyota, Tsuyoshi; Takahashi, Yuki; Watcharanurak, Kanitta; Nishikawa, Makiya; Ohara, Saori; Ando, Mitsuru; Watanabe, Yoshihiko; Takakura, Yoshinobu

2014-05-05

Tumor-associated macrophages (TAMs) negatively affect the therapeutic effects of anticancer agents. To examine the role of TAMs in interferon (IFN)-γ gene therapy, we selected two types of solid tumors, which varied in the number of TAMs, and investigated the effects of IFN-γ gene transfer on tumor growth. Many TAMs were detected in the solid tumors of murine adenocarcinoma colon-26 cells, whereas few TAMs were detected in murine melanoma B16-BL6 cells. IFN-γ gene transfer hardly suppressed the growth of colon-26 tumors, whereas it was effective in suppressing the growth of B16-BL6 tumors. The antiproliferative effects of IFN-γ on cultured colon-26 cells were similar to those on cultured B16-BL6 cells. To evaluate the role of TAMs, we injected clodronate liposomes (CLs) modified with poly(ethylene glycol) (PEG) to functionally deplete TAMs in tumor-bearing mice. Repeated injections of PEG-CLs significantly retarded the growth of colon-26 tumors and combination with IFN-γ gene transfer further inhibited the growth. In contrast, PEG-CLs hardly retarded the growth of B16-BL6 tumors. These results clearly indicate that TAM depletion is effective in enhancing the therapeutic effect of IFN-γ in TAM-repleted and IFN-γ-resistant tumors.

State-of-the-Art Management for the Patient with Castration-Resistant Prostate Cancer in 2012.

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Sartor, Oliver

2012-01-01

Much progress has been made in metastatic castration-resistant prostate cancer (CRPC), and multiple new U.S. Food and Drug Administration (FDA)-approved survival-prolonging drugs are now available. In 2004, docetaxel/prednisone was the first therapy shown to prolong survival. In 2010 and 2011, sipuleucel-T, cabazitaxel/prednisone, and abiraterone/prednisone were FDA approved. Two new agents, radium-223 and MDV-3100, have recently reported large phase III trials prolonging overall survival and will be submitted for regulatory approval in 2012. One can now begin to ask, is there an optimal sequence for therapies in metastatic CRPC? Despite the recent progress, there is much we do not know and virtually no information on this important question. We know that abiraterone/prednisone and cabazitaxel/prednisone are appropriate choices for a patient after receiving docetaxel, but we do not know what, if anything, represents the optimal sequence for abiraterone and cabazitaxel. In fact we do not understand how one therapy may affect the response to a subsequent therapy. We are also aware that the pre- and postdocetaxel spaces represent regulatory rather than biologic divisions. In addition, despite the proven role of docetaxel/prednisone, many patients with CRPC are not considered to be suitable for chemotherapy, and worldwide many never receive any form of chemotherapy. What is the optimal management for these patients? Taken together it is reasonable to assess patient preferences, prior therapies and response/tolerance to prior therapies, burden of disease, comorbidities, current symptoms, drug toxicities, out-of-pocket costs, etc., in clinical decision making. Given the many factors we do not know, it is hard to be dogmatic in approaching the therapeutic options for the patient with CRPC. We will likely soon move beyond the current sequencing paradigm and begin to assess new combinations in a systematic and rational fashion. Perhaps one day, in the not too distant future

[Vitamin-resistant rickets cured by removal of a bone tumor. Review of the literature].

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François, S; Lefort, G; Poli-Merol, M L; Gaillard, D; Roussel, B; Sulmont, V; Daoud, S

1997-01-01

Rickets secondary to bone or soft tissue tumors are rare in children. Majority of the reported cases occurred in adults older than thirty. This entity can be cured after tumor removal. The authors present a case in a ten year boy and literature review. A ten year boy complained of diffuse bone and muscle weakness for two years. A diagnosis of arthritis was made but the patient continued to complain. Serum calcium level was normal (2.33 mmol/l), phosphorus was very low (0.43 mmol/l), serum alkaline phosphatase was high, parathyroid hormone and vitamin D level were normal. Urinalysis showed abnormal phosphate excretion. The absence of malabsorption, no family history of rickets or hypophosphatermy presence of a marked excess of urinary phosphate, very low serum phosphate and normal serum calcium, vitamin D and parathyroid hormone levels led us to consider a diagnosis of tumor induced osteomalacia. Radiographs showed a large round radiolucent lesion in the left superior pubic ramus and generalized demineralisation. We performed a complete tumor resection and the space was filled with bone graft. On histopathologic examination it was a benign mesenchymal tumor. Rapid reversal of biochemical anomalies, radiographs anomalies and clinical manifestation were observed after complete tumor resection. The authors have described the tumor, the osteomalacia and the pathogenesis of tumor rickets. Histologically the most common causative tumors were vascular tumors, mesenchymal tumors and non ossifying tumors. The tumor were of bone or soft tissue origin. Clinical symptoms were muscular weakness, bone and muscle pain. Biochemically there is a very low phosphate level, a normal serum calcium level as well as a normal vitamin D and PTH level. There is a significant high level of urinal phosphate. The mechanism proposed to explain oncogenic osteomalacia includes tumor secretion of phosphaturic substance other than PTH and calcitonin. Another hypothesis is a substance interfering

Starvation reveals the cause of infection-induced castration and gigantism.

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Cressler, Clayton E; Nelson, William A; Day, Troy; McCauley, Edward

2014-10-07

Parasites often induce life-history changes in their hosts. In many cases, these infection-induced life-history changes are driven by changes in the pattern of energy allocation and utilization within the host. Because these processes will affect both host and parasite fitness, it can be challenging to determine who benefits from them. Determining the causes and consequences of infection-induced life-history changes requires the ability to experimentally manipulate life history and a framework for connecting life history to host and parasite fitness. Here, we combine a novel starvation manipulation with energy budget models to provide new insights into castration and gigantism in the Daphnia magna-Pasteuria ramosa host-parasite system. Our results show that starvation primarily affects investment in reproduction, and increasing starvation stress reduces gigantism and parasite fitness without affecting castration. These results are consistent with an energetic structure where the parasite uses growth energy as a resource. This finding gives us new understanding of the role of castration and gigantism in this system, and how life-history variation will affect infection outcome and epidemiological dynamics. The approach of combining targeted life-history manipulations with energy budget models can be adapted to understand life-history changes in other disease systems.

Starvation reveals the cause of infection-induced castration and gigantism

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Cressler, Clayton E.; Nelson, William A.; Day, Troy; McCauley, Edward

2014-01-01

Parasites often induce life-history changes in their hosts. In many cases, these infection-induced life-history changes are driven by changes in the pattern of energy allocation and utilization within the host. Because these processes will affect both host and parasite fitness, it can be challenging to determine who benefits from them. Determining the causes and consequences of infection-induced life-history changes requires the ability to experimentally manipulate life history and a framework for connecting life history to host and parasite fitness. Here, we combine a novel starvation manipulation with energy budget models to provide new insights into castration and gigantism in the Daphnia magna–Pasteuria ramosa host–parasite system. Our results show that starvation primarily affects investment in reproduction, and increasing starvation stress reduces gigantism and parasite fitness without affecting castration. These results are consistent with an energetic structure where the parasite uses growth energy as a resource. This finding gives us new understanding of the role of castration and gigantism in this system, and how life-history variation will affect infection outcome and epidemiological dynamics. The approach of combining targeted life-history manipulations with energy budget models can be adapted to understand life-history changes in other disease systems. PMID:25143034

Estrogen receptor positive breast tumors resist chemotherapy by the overexpression of P53 in Cancer Stem Cells

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Fatma Ashour

2018-06-01

Full Text Available Background and Objectives: Breast cancer (BC is classified according to estrogen receptor (ER status into ER+ and ER− tumors. ER+ tumors have a worse response to chemotherapy compared to ER− tumors. BCL-2, TP53, BAX and NF-ΚB are involved in drug resistance in the ER+ tumors. Recently it was shown that Cancer Stem Cells (CSCs play an important role in drug resistance. In this study we tested the hypothesis that CSCs of the ER+ tumors resist drug through the overexpression of BCL-2, TP53, BAX and NF-ΚB. Methods: CSCs were isolated by anoikis resistance assay from MCF7 (ER+ and MDA-MB-231 (ER− cell lines. Isolated CSCs were treated with doxorubicin (DOX and the mRNA expression levels of BCL-2, TP53, BAX and NFKB were investigated by quantitative real time PCR (qPCR with and without treatment. Results: BCL-2, BAX and NF-ΚB showed decreased expression in MCF7 bulk cancer cells after DOX treatment whereas only BCL-2 and BAX showed decreased expression in MDA-MB-231 bulk cancer cells. Interestingly TP53 was the only gene showed a considerable increase in its expression in CSCs of the ER+ MCF7 cell line compared to bulk cancer cells. Moreover, TP53 was the only gene showing exceptionally higher level of expression in MCF7-CSCs compared to MDA-MB-231-CSCs. Conclusion: Our results suggest that CSCs in the ER+ cells escape the effect of DOX treatment by the elevation of p53 expression. Keywords: Breast cancer, Cancer Stem Cells, Drug resistance, Estrogen receptors

The necrotic signal induced by mycophenolic acid overcomes apoptosis-resistance in tumor cells.

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Gwendaline Guidicelli

Full Text Available BACKGROUND: The amount of inosine monophosphate dehydrogenase (IMPDH, a pivotal enzyme for the biosynthesis of the guanosine tri-phosphate (GTP, is frequently increased in tumor cells. The anti-viral agent ribavirin and the immunosuppressant mycophenolic acid (MPA are potent inhibitors of IMPDH. We recently showed that IMPDH inhibition led to a necrotic signal requiring the activation of Cdc42. METHODOLOGY/PRINCIPAL FINDINGS: Herein, we strengthened the essential role played by this small GTPase in the necrotic signal by silencing Cdc42 and by the ectopic expression of a constitutive active mutant of Cdc42. Since resistance to apoptosis is an essential step for the tumorigenesis process, we next examined the effect of the MPA-mediated necrotic signal on different tumor cells demonstrating various mechanisms of resistance to apoptosis (Bcl2-, HSP70-, Lyn-, BCR-ABL-overexpressing cells. All tested cells remained sensitive to MPA-mediated necrotic signal. Furthermore, inhibition of IMPDH activity in Chronic Lymphocytic Leukemia cells was significantly more efficient at eliminating malignant cells than apoptotic inducers. CONCLUSIONS/SIGNIFICANCE: These findings indicate that necrosis and apoptosis are split signals that share few if any common hub of signaling. In addition, the necrotic signaling pathway induced by depletion of the cellular amount of GTP/GDP would be of great interest to eliminate apoptotic-resistant tumor cells.

Resistance exercise attenuates skeletal muscle oxidative stress, systemic pro-inflammatory state, and cachexia in Walker-256 tumor-bearing rats.

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Padilha, Camila Souza; Borges, Fernando Henrique; Costa Mendes da Silva, Lilian Eslaine; Frajacomo, Fernando Tadeu Trevisan; Jordao, Alceu Afonso; Duarte, José Alberto; Cecchini, Rubens; Guarnier, Flávia Alessandra; Deminice, Rafael

2017-09-01

The aim of this study was to investigate the effects of resistance exercise training (RET) on oxidative stress, systemic inflammatory markers, and muscle wasting in Walker-256 tumor-bearing rats. Male (Wistar) rats were divided into 4 groups: sedentary controls (n = 9), tumor-bearing (n = 9), exercised (n = 9), and tumor-bearing exercised (n = 10). Exercised and tumor-bearing exercised rats were exposed to resistance exercise of climbing a ladder apparatus with weights tied to their tails for 6 weeks. The physical activity of control and tumor-bearing rats was confined to the space of the cage. After this period, tumor-bearing and tumor-bearing exercised animals were inoculated subcutaneously with Walker-256 tumor cells (11.0 × 10 7 cells in 0.5 mL of phosphate-buffered saline) while control and exercised rats were injected with vehicle. Following inoculation, rats maintained resistance exercise training (exercised and tumor-bearing exercised) or sedentary behavior (control and tumor-bearing) for 12 more days, after which they were euthanized. Results showed muscle wasting in the tumor-bearing group, with body weight loss, increased systemic leukocytes, and inflammatory interleukins as well as muscular oxidative stress and reduced mTOR signaling. In contrast, RET in the tumor-bearing exercised group was able to mitigate the reduced body weight and muscle wasting with the attenuation of muscle oxidative stress and systemic inflammatory markers. RET also prevented loss of muscle strength associated with tumor development. RET, however, did not prevent the muscle proteolysis signaling via FBXO32 gene messenger RNA expression in the tumor-bearing group. In conclusion, RET performed prior tumor implantation prevents cachexia development by attenuating tumor-induced systemic pro-inflammatory condition with muscle oxidative stress and muscle damage.

Performance of intact and castrated beef cattle in an intensive croppasture rotation system

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Tercilio Turini

2015-07-01

Full Text Available This research had as objective to evaluate the performance of intact or castrated beef cattle in a croppasture rotation system. The experiment was conducted during 2004 and 2005, and carried out at the Cooperativa Agropecuária Mourãoense (COAMO Experimental Farm, in Campo Mourão city, Paraná state. It was used a completely randomized design, with two treatments, intact or castrated. Forty ½Angus+½Nelore crossbred animals, with average age of nine months, were used. Half of the animals were castrated at weaning, and the other half was kept intact. Pasture was composed of two areas. The winter field, established after soybean crop, was composed by a mixture of black oat (Avena strigosa and Italian ryegrass (Lolium multiforum. The summer field was composed by stargrass (Cynodon nlemfuensis and Mombaça grass (Panicum maximum. During the winter time it was used a continues grazing system, with regulator animals (put and take, and during the summer an intensive rotational system, with regulator animals and fixed grazing period. Intact animals presented higher average daily weight gain (0.907 vs 0.698 kg, slaughter weight (490.9 vs 442.2 kg, and hot carcass weight (250.2 vs 232.6 kg. Slaughter age was influenced by sexual condition, being lesser in the intact animals. Carcass dressing percentage was similar for the groups. Castrated animals showed better finishing fat cover and backfat thickness (3.45 vs 2.70 mm compared to intact ones. Therefore, it can be concluded that intact animals presents better performance than castrated ones when finished in an intensive crop-pasture rotation system, however, they may not present the minimum required fat cover, when slaughter at young ages.

[Pinealectomy and early castration in the female Wistar rat].

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Slama-Scemama, A

1976-05-17

Pinealectomy does not significantly modify the level of pituitary and plasma gonadotropins in intact and in castrated female Rats from brith to 75 days of age. Only the weight of the thyroid gland is higher in pinealectomized rats.

Splenic angiomyxoma with intravascular tumor embolus in a dog: a case report.

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Lee, Eun-Mi; Kim, Ah-Young; Lee, Eun-Joo; Park, Jin-Kyu; Kim, Tae-Hwan; Park, Se-Il; Jeong, Kyu-Shik

2016-07-01

A 13-year-old castrated male Yorkshire terrier dog had a soft splenic mass, which measured 11 cm in the greatest diameter. Microscopically, the parenchyma of the spleen was completely replaced by myxoid substances. Numerous spindle and stellate cells were loosely arranged in the myxoid stroma, and variable vessels of variable sizes were observed in a loose matrix with poorly defined margins. Immunohistochemical analysis showed that tumor cells were positive for desmin and alpha-SMA, but negative for S-100. Interestingly, intravascular tumor embolus with positive α-SMA expression was observed. This case is meaningful, because angiomyxoma, a rare tumor of dogs, occurs in the spleen. Even in human cases, splenic angiomyxoma was not reported.

Phenotypic and genetic heterogeneity of tumor tissue and circulating tumor cells in patients with metastatic castrationresistant prostate cancer: a report from the PETRUS prospective study

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Massard, Christophe; Oulhen, Marianne; Le Moulec, Sylvestre; Auger, Nathalie; Foulon, Stéphanie; Abou-Lovergne, Aurélie; Billiot, Fanny; Valent, Alexander; Marty, Virginie; Loriot, Yohann; Fizazi, Karim; Vielh, Philippe; Farace, Francoise

2016-01-01

Molecular characterization of cancer samples is hampered by tumor tissue availability in metastatic castration-resistant prostate cancer (mCRPC) patients. We reported the results of prospective PETRUS study of biomarker assessment in paired primary prostatic tumors, metastatic biopsies and circulating tumor cells (CTCs). Among 54 mCRPC patients enrolled, 38 (70%) had biopsies containing more than 50% tumour cells. 28 (52%) patients were analyzed for both tissue samples and CTCs. FISH for AR-amplification and TMPRSS2-ERG translocation were successful in 54% and 32% in metastatic biopsies and primary tumors, respectively. By comparing CellSearch and filtration (ISET)-enrichment combined to four color immunofluorescent staining, we showed that CellSearch and ISET isolated distinct subpopulations of CTCs: CTCs undergoing epithelial-to-mesenchymal transition, CTC clusters and large CTCs with cytomorphological characteristics but no detectable markers were isolated using ISET. Epithelial CTCs detected by the CellSearch were mostly lost during the ISET-filtration. AR-amplification was detected in CellSearch-captured CTCs, but not in ISET-enriched CTCs which harbor exclusively AR gain of copies. Eighty-eight percent concordance for ERG-rearrangement was observed between metastatic biopsies and CTCs even if additional ERG-alteration patterns were detected in ISET-enriched CTCs indicating a higher heterogeneity in CTCs. Molecular screening of metastatic biopsies is achievable in a multicenter context. Our data indicate that CTCs detected by the CellSearch and the ISET-filtration systems are not only phenotypically but also genetically different. Close attention must be paid to CTC characterization since neither approach tested here fully reflects the tremendous phenotypic and genetic heterogeneity present in CTCs from mCRPC patients. PMID:27391263

Factors affecting the local control of stereotactic body radiotherapy for lung tumors including primary lung cancer and metastatic lung tumors

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Hamamoto, Yasushi; Kataoka, Masaaki; Yamashita, Motohiro

2012-01-01

The purpose of this study was to identify factors affecting local control of stereotactic body radiotherapy (SBRT) for lung tumors including primary lung cancer and metastatic lung tumors. Between June 2006 and June 2009, 159 lung tumors in 144 patients (primary lung cancer, 128; metastatic lung tumor, 31) were treated with SBRT with 48-60 Gy (mean 50.1 Gy) in 4-5 fractions. Higher doses were given to larger tumors and metastatic tumors in principle. Assessed factors were age, gender, tumor origin (primary vs. metastatic), histological subtype, tumor size, tumor appearance (solid vs. ground glass opacity), maximum standardized uptake value of positron emission tomography using 18 F-fluoro-2-deoxy-D-glucose, and SBRT doses. Follow-up time was 1-60 months (median 18 months). The 1-, 2-, and 3-year local failure-free rates of all lesions were 90, 80, and 77%, respectively. On univariate analysis, metastatic tumors (p<0.0001), solid tumors (p=0.0246), and higher SBRT doses (p=0.0334) were the statistically significant unfavorable factors for local control. On multivariate analysis, only tumor origin was statistically significant (p=0.0027). The 2-year local failure-free rates of primary lung cancer and metastatic lung tumors were 87 and 50%, respectively. A metastatic tumor was the only independently significant unfavorable factor for local control after SBRT. (author)

Correlation between LH secretion in castrated rats with cellular proliferation and synthesis of DNA in the anterior pituitary gland.

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Romano, M I; Machiavelli, G A; Pérez, R L; Carricarte, V; Burdman, J A

1984-07-01

The relationship between the release of LH and the synthesis of DNA was studied in the anterior pituitary gland of castrated rats. Cell types were characterized immunocytochemically. Castration significantly (P less than 0.01) increased the concentration of LH in serum (1326%) and the incorporation of [3H]thymidine into pituitary DNA (72%). This was accompanied by an increment in the activity of the enzyme DNA polymerase-alpha (58%) and in the number of mitoses (from 2 +/- 0.1/mm2 in intact rats to 21 +/- 0.8/mm2 15 days after castration). Only 20% of the mitoses found in the pituitary gland of castrated rats were positively stained with the antiserum against the beta-subunit of LH. The other 80% did not stain either with LH antiserum or with antisera against the other pituitary hormones. There was a significant (P less than 0.01) increase in the number of LH cells in castrated rats (48%). All the changes produced in the anterior pituitary gland after castration were prevented by the administration of dihydrotestosterone. The results demonstrate that a stimulation of LH release is followed by an increase of DNA synthesis and cell proliferation of gonadotrophs in the anterior pituitary gland.

Chemical castration in cattle with intratesticular injection of sodium chloride: Effects on stress and inflammatory markers.

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Oliveira, Fernando C; Ferreira, Carlos E R; Haas, Cristina S; Oliveira, Leonardo G; Mondadori, Rafael G; Schneider, Augusto; Rovani, Monique T; Gonçalves, Paulo B D; Vieira, Arnaldo D; Gasperin, Bernardo G; Lucia, Thomaz

2017-03-01

Intratesticular injection (ITI) of sodium chloride (NaCl) is efficient for chemical castration of young calves, but its effects on calves welfare are unknown. Two experiments were conducted to evaluate the effects of ITI of 20% NaCl on stress and inflammatory markers in calves less than 20 days old and to assess the efficiency of ITI of 30% NaCl in 5 months old calves. In Experiment 1, control calves were only restrained and compared to calves submitted to castration through surgery (SC) and ITI with 20% NaCl (n = 9/group). No differences were observed for the eye corner temperature measured by thermography from 60 s before to 60 s after the procedures (P > 0.05). In the SC group, acute serum cortisol levels increased at 30 and 60 min after the procedure, but increased levels in the ITI group occurred only at 30 min (P  0.05). Scrotal temperature was higher at D1 in the SC group than for the other groups, but lowest at D4 compared to the control (both P castration through ITI of 20% NaCl in young calves was followed by slight stress and inflammatory responses compared to surgical castration. However, ITI of 30% NaCl was ineffective for chemical castration of 5 months old calves. Copyright © 2016 Elsevier Inc. All rights reserved.

Estrogen receptor signaling in prostate cancer: Implications for carcinogenesis and tumor progression.

Science.gov (United States)

Bonkhoff, Helmut

2018-01-01

The androgen receptor (AR) is the classical target for prostate cancer prevention and treatment, but more recently estrogens and their receptors have also been implicated in prostate cancer development and tumor progression. Recent experimental and clinical data were reviewed to elucidate pathogenetic mechanisms how estrogens and their receptors may affect prostate carcinogenesis and tumor progression. The estrogen receptor beta (ERβ) is the most prevalent ER in the human prostate, while the estrogen receptor alpha (ERα) is restricted to basal cells of the prostatic epithelium and stromal cells. In high grade prostatic intraepithelial neoplasia (HGPIN), the ERα is up-regulated and most likely mediates carcinogenic effects of estradiol as demonstrated in animal models. The partial loss of the ERβ in HGPIN indicates that the ERβ acts as a tumor suppressor. The tumor promoting function of the TMPRSS2-ERG fusion, a major driver of prostate carcinogenesis, is triggered by the ERα and repressed by the ERβ. The ERβ is generally retained in hormone naïve and metastatic prostate cancer, but is partially lost in castration resistant disease. The progressive emergence of the ERα and ERα-regulated genes (eg, progesterone receptor (PR), PS2, TMPRSS2-ERG fusion, and NEAT1) during prostate cancer progression and hormone refractory disease suggests that these tumors can bypass the AR by using estrogens and progestins for their growth. In addition, nongenomic estrogen signaling pathways mediated by orphan receptors (eg, GPR30 and ERRα) has also been implicated in prostate cancer progression. Increasing evidences demonstrate that local estrogen signaling mechanisms are required for prostate carcinogenesis and tumor progression. Despite the recent progress in this research topic, the translation of the current information into potential therapeutic applications remains highly challenging and clearly warrants further investigation. © 2017 Wiley Periodicals, Inc.

Intratesticular hypertonic sodium chloride solution treatment as a method of chemical castration in cattle.

Science.gov (United States)

Neto, Olmiro Andrade; Gasperin, Bernardo G; Rovani, Monique T; Ilha, Gustavo F; Nóbrega, Janduí E; Mondadori, Rafael G; Gonçalves, Paulo B D; Antoniazzi, Alfredo Q

2014-10-15

Castration of male calves is necessary for trading to facilitate handling and prevent reproduction. However, some methods of castration are traumatic and lead to economic losses because of infection and myiasis. The objective of the present study was to evaluate the efficiency of intratesticular injection (ITI) of hypertonic sodium chloride (NaCl; 20%) solution in male calf castration during the first weeks of life. Forty male calves were allocated to one of the following experimental groups: negative control-surgically castrated immediately after birth; positive control -intact males; G1-ITI from 1- to 5-day old; G2-ITI from 15- to 20-day old; and G3-ITI from 25- to 30-day old. Intratesticular injection induced coagulative necrosis of Leydig cells and seminiferous tubules leading to extensive fibrosis. Testosterone secretion and testicular development were severely impaired in 12-month-old animals from G1 and G2 groups (P<0.05), in which no testicular structure and sperm cells were observed during breeding soundness evaluation. Rectal and scrotal temperatures were not affected by different procedures. In conclusion, ITI of hypertonic NaCl solution induces sterility and completely suppresses testosterone secretion when performed during the first 20 days of life. Copyright © 2014 Elsevier Inc. All rights reserved.

Tumor suppressor WWOX and p53 alterations and drug resistance in glioblastomas

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Ming-Fu eChiang

2013-03-01

Full Text Available Tumor suppressor p53 are frequently mutated in glioblastomas (GBMs and appears to contribute, in part, to resistance to temozolomide and therapeutic drugs. WW domain-containing oxidoreductase WWOX (FOR or WOX1 is a proapoptotic protein and is considered as a tumor suppressor. Loss of WWOX gene expression is frequently seen in malignant cancer cells due to promoter hypermethylation, genetic alterations, and translational blockade. Intriguingly, ectopic expression of wild type WWOX preferentially induces apoptosis in human glioblastoma cells harboring mutant p53. WWOX is known to physically bind and stabilize wild type p53. Here, we provide an overview for the updated knowledge in p53 and WWOX, and postulate a potential scenarios that wild type and mutant p53, or isoforms, modulate the apoptotic function of WWOX. We propose that triggering WWOX activation by therapeutic drugs under p53 functional deficiency is needed to overcome TMZ resistance and induce GBM cell death.

Post hoc analysis of Japanese patients from the placebo-controlled PREVAIL trial of enzalutamide in patients with chemotherapy-naive, metastatic castration-resistant prostate cancer-updated results.

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Kimura, Go; Ueda, Takeshi

2017-03-01

A post hoc analysis of interim results from PREVAIL, a Phase III, double-blind, placebo-controlled trial of men with metastatic castration-resistant prostate cancer, demonstrated that the treatment effects, safety and pharmacokinetics of enzalutamide in Japanese patients were generally consistent with those of the overall population. A recent longer term analysis of PREVAIL demonstrated continued benefit of enzalutamide treatment over placebo. Here, we report results from a post hoc analysis of Japanese patients enrolled in PREVAIL at the prespecified number of deaths for the final analysis. In Japanese patients, enzalutamide reduced the risk of death by 35% (hazard ratio, 0.65; 95% confidence interval, 0.28-1.51) and the risk of investigator-assessed radiographic progression or death by 60% (hazard ratio, 0.40; 95% confidence interval, 0.18-0.90). These results show that treatment effects and safety in Japanese patients in the final analysis of PREVAIL continued to be generally consistent with those of the overall population. © The Author 2016. Published by Oxford University Press.

Empirical support for optimal virulence in a castrating parasite.

Directory of Open Access Journals (Sweden)

Knut Helge Jensen

2006-07-01

Full Text Available The trade-off hypothesis for the evolution of virulence predicts that parasite transmission stage production and host exploitation are balanced such that lifetime transmission success (LTS is maximised. However, the experimental evidence for this prediction is weak, mainly because LTS, which indicates parasite fitness, has been difficult to measure. For castrating parasites, this simple model has been modified to take into account that parasites convert host reproductive resources into transmission stages. Parasites that kill the host too early will hardly benefit from these resources, while postponing the killing of the host results in diminished returns. As predicted from optimality models, a parasite inducing castration should therefore castrate early, but show intermediate levels of virulence, where virulence is measured as time to host killing. We studied virulence in an experimental system where a bacterial parasite castrates its host and produces spores that are not released until after host death. This permits estimating the LTS of the parasite, which can then be related to its virulence. We exposed replicate individual Daphnia magna (Crustacea of one host clone to the same amount of bacterial spores and followed individuals until their death. We found that the parasite shows strong variation in the time to kill its host and that transmission stage production peaks at an intermediate level of virulence. A further experiment tested for the genetic basis of variation in virulence by comparing survival curves of daphniids infected with parasite spores obtained from early killing versus late killing infections. Hosts infected with early killer spores had a significantly higher death rate as compared to those infected with late killers, indicating that variation in time to death was at least in part caused by genetic differences among parasites. We speculate that the clear peak in lifetime reproductive success at intermediate killing times

Retrotransposon Targeting of Tumor Cells

National Research Council Canada - National Science Library

Wu, Dongdong; DeVaux, George

2005-01-01

.... Cancer gene therapy techniques include oncogene inactivation, tumor suppressor gene replacement, inhibition of angiogenesis, immunopotentiation, molecular chemotherapy, and transfer of drug resistance genes...

Molecular mechanisms of drug resistance and tumor promotion involving mammalian ribonucleotide reductase

Energy Technology Data Exchange (ETDEWEB)

Choy, B.B.K.

1991-01-01

Mammalian ribonucleotide reductase is a highly regulated, rate-limiting activity responsible for converting ribonucleoside diphosphates to the deoxyribonucleotide precursors of DNA. The enzyme consists of two nonidentical proteins called M1 and M2, both of which are required for activity. Hydroxyurea is an antitumor agent which inhibits ribonucleotide reductase by interacting with the M2 component specifically at a unique tyrosyl free radical. Studies were conducted on a series of drug resistant mouse cell lines, selected by a step-wise procedure for increasing levels of resistance to the cytotoxic effects of hydroxyurea. Each successive drug selection step leading to the isolation of highly resistant cells was accompanied by stable elevations in cellular resistance and ribonucleotide reductase activity. The drug resistant cell lines exhibited gene amplification of the M2 gene, elevated M2 mRNA, and M2 protein. In addition to M2 gene amplification, posttranscriptional modulation also occurred during the drug selection. Studies of the biosynthesis rates with exogenously added iron suggest a role for iron in regulating the level of M2 protein when cells are cultured in the presence of hydroxyurea. The hydroxyurea-inactivated ribonucleotide reductase protein M2 has a destabilized iron centre, which readily releases iron. Altered expression of ferritin appears to be required for the development of hydroxyurea resistance in nammalian cells. The results show an interesting relationship between the expressions of ribonucleotide reductase and ferritin. The phorbol ester tumor promoter, TPA, is also able to alter the expression of M2. TPA was able to induce M2 mRNA levels transiently up to 18-fold within 1/2 hour. This rapid and large elevation of ribonucleotide reductase suggests that the enzyme may play a role in tumor promotion. Studies of the M2 promoter region were undertaken to better understand the mechanism of TPA induction of M2.

Systemic therapy in men with metastatic castration-resistant prostate cancer:American Society of Clinical Oncology and Cancer Care Ontario clinical practice guideline.

Science.gov (United States)

Basch, Ethan; Loblaw, D Andrew; Oliver, Thomas K; Carducci, Michael; Chen, Ronald C; Frame, James N; Garrels, Kristina; Hotte, Sebastien; Kattan, Michael W; Raghavan, Derek; Saad, Fred; Taplin, Mary-Ellen; Walker-Dilks, Cindy; Williams, James; Winquist, Eric; Bennett, Charles L; Wootton, Ted; Rumble, R Bryan; Dusetzina, Stacie B; Virgo, Katherine S

2014-10-20

To provide treatment recommendations for men with metastatic castration-resistant prostate cancer (CRPC). The American Society of Clinical Oncology and Cancer Care Ontario convened an expert panel to develop evidence-based recommendations informed by a systematic review of the literature. When added to androgen deprivation, therapies demonstrating improved survival, improved quality of life (QOL), and favorable benefit-harm balance include abiraterone acetate/prednisone, enzalutamide, and radium-223 ((223)Ra; for men with predominantly bone metastases). Improved survival and QOL with moderate toxicity risk are associated with docetaxel/prednisone. For asymptomatic/minimally symptomatic men, improved survival with unclear QOL impact and low toxicity are associated with sipuleucel-T. For men who previously received docetaxel, improved survival, unclear QOL impact, and moderate to high toxicity risk are associated with cabazitaxel/prednisone. Modest QOL benefit (without survival benefit) and high toxicity risk are associated with mitoxantrone/prednisone after docetaxel. No benefit and excess toxicity are observed with bevacizumab, estramustine, and sunitinib. Continue androgen deprivation (pharmaceutical or surgical) indefinitely. Abiraterone acetate/prednisone, enzalutamide, or (223)Ra should be offered; docetaxel/prednisone should also be offered, accompanied by discussion of toxicity risk. Sipuleucel-T may be offered to asymptomatic/minimally symptomatic men. For men who have experienced progression with docetaxel, cabazitaxel may be offered, accompanied by discussion of toxicity risk. Mitoxantrone may be offered, accompanied by discussion of limited clinical benefit and toxicity risk. Ketoconazole or antiandrogens (eg, bicalutamide, flutamide, nilutamide) may be offered, accompanied by discussion of limited known clinical benefit. Bevacizumab, estramustine, and sunitinib should not be offered. There is insufficient evidence to evaluate optimal sequences or

Prostate-specific antigen kinetics and outcomes in patients with bone metastases from castration-resistant prostate cancer treated with or without zoledronic acid.

Science.gov (United States)

Saad, Fred; Segal, Scott; Eastham, James

2014-01-01

Zoledronic acid (ZOL) is a standard therapy for the prevention of skeletal-related events (SREs) in patients with castration-resistant prostate cancer (CRPC). Although prostate-specific antigen (PSA) is an established marker for monitoring prostate cancer patients, correlations between PSA and disease outcomes during ZOL therapy are unclear. To evaluate the relationships among PSA kinetics, bone-directed therapy with ZOL, and clinical outcomes in men with bone metastases from CRPC using a ZOL phase 3 trial database. Exploratory analyses from a phase 3 trial in men with bone metastases from CRPC (n=643) randomized to ZOL or placebo every 3 wk. PSA levels during the first 3 mo of the study were evaluated in linear and logarithmic (log) models stratified using prognostic factors established in a ZOL phase 3 trial and a CRPC nomogram. Relative risks of SREs, bone disease progression (BDP), and death were calculated per 1 log (nanograms per milliliter) PSA increase. Baseline PSA models used the study median (PSA: 77.3 ng/ml) as the high/low cut-off point. A total of 202 placebo- and 434 ZOL-treated patients were assessable. In both groups, PSA increases correlated with significantly increased risks of death, BDP, and first SRE. In the placebo and ZOL groups, associated increases in risk per 1 log (nanograms per milliliter) PSA increase were 29% (p<0.0001) and 10% (p<0.0074), respectively, for BDP, and 24% (p=0.0010) and 13% (p=0.0079), respectively, for first SRE. Limitations include the retrospective nature of these analyses and the potential confounding effects of concurrent antineoplastic therapies. PSA is an important prognostic tool for survival in patients with bone metastases from CRPC, and these analyses show that PSA is also prognostic for BDP and SREs regardless of bone-targeted therapy. Copyright © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Castration of male livestock and the potential of immunocastration to ...

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2017-09-15

Sep 15, 2017 ... Abstract. Growing consumer awareness about animal welfare has led to the assessment of the impact of .... the incidence and associated effects of aggressive and sexual behaviour (Aasen, 2000). ... Motivation for castration.

Phenotype switching : tumor cell plasticity as a resistance mechanism and target for therapy

NARCIS (Netherlands)

Kemper, K.; de Goeje, P.L.; Peeper, D.S.; van Amerongen, R.

2014-01-01

Mutations in BRAF are present in the majority of patients with melanoma, rendering these tumors sensitive to targeted therapy with BRAF and MEK inhibitors. Unfortunately, resistance almost invariably develops. Recently, a phenomenon called "phenotype switching" has been identified as an escape

Cellular androgen content influences enzalutamide agonism of F877L mutant androgen receptor

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Coleman, Daniel J.; Van Hook, Kathryn; King, Carly J.; Schwartzman, Jacob; Lisac, Robert; Urrutia, Joshua; Sehrawat, Archana; Woodward, Josha; Wang, Nicholas J.; Gulati, Roman; Thomas, George V.; Beer, Tomasz M.; Gleave, Martin; Korkola, James E.; Gao, Lina; Heiser, Laura M.; Alumkal, Joshi J.

2016-01-01

Prostate cancer is the most commonly diagnosed and second-most lethal cancer among men in the United States. The vast majority of prostate cancer deaths are due to castration-resistant prostate cancer (CRPC) – the lethal form of the disease that has progressed despite therapies that interfere with activation of androgen receptor (AR) signaling. One emergent resistance mechanism to medical castration is synthesis of intratumoral androgens that activate the AR. This insight led to the development of the AR antagonist enzalutamide. However, resistance to enzalutamide invariably develops, and disease progression is nearly universal. One mechanism of resistance to enzalutamide is an F877L mutation in the AR ligand-binding domain that can convert enzalutamide to an agonist of AR activity. However, mechanisms that contribute to the agonist switch had not been fully clarified, and there were no therapies to block AR F877L. Using cell line models of castration-resistant prostate cancer (CRPC), we determined that cellular androgen content influences enzalutamide agonism of mutant F877L AR. Further, enzalutamide treatment of AR F877L-expressing cell lines recapitulated the effects of androgen activation of F877L AR or wild-type AR. Because the BET bromodomain inhibitor JQ-1 was previously shown to block androgen activation of wild-type AR, we tested JQ-1 in AR F877L-expressing CRPC models. We determined that JQ-1 suppressed androgen or enzalutamide activation of mutant F877L AR and suppressed growth of mutant F877L AR CRPC tumors in vivo, demonstrating a new strategy to treat tumors harboring this mutation. PMID:27276681

Influence of Multiple Infection and Relatedness on Virulence: Disease Dynamics in an Experimental Plant Population and Its Castrating Parasite

Science.gov (United States)

Buono, Lorenza; López-Villavicencio, Manuela; Shykoff, Jacqui A.; Snirc, Alodie; Giraud, Tatiana

2014-01-01

The level of parasite virulence, i.e., the decrease in host's fitness due to a pathogen, is expected to depend on several parameters, such as the type of the disease (e.g., castrating or host-killing) and the prevalence of multiple infections. Although these parameters have been extensively studied theoretically, few empirical data are available to validate theoretical predictions. Using the anther smut castrating disease on Silene latifolia caused by Microbotryum lychnidis-dioicae, we studied the dynamics of multiple infections and of different components of virulence (host death, non-recovery and percentage of castrated stems) during the entire lifespan of the host in an experimental population. We monitored the number of fungal genotypes within plants and their relatedness across five years, using microsatellite markers, as well as the rates of recovery and host death in the population. The mean relatedness among genotypes within plants remained at a high level throughout the entire host lifespan despite the dynamics of the disease, with recurrent new infections. Recovery was lower for plants with multiple infections compared to plants infected by a single genotype. As expected for castrating parasites, M. lychnidis-dioicae did not increase host mortality. Mortality varied across years but was generally lower for plants that had been diseased the preceding year. This is one of the few studies to have empirically verified theoretical expectations for castrating parasites, and to show particularly i) that castrated hosts live longer, suggesting that parasites can redirect resources normally used in reproduction to increase host lifespan, lengthening their transmission phase, and ii) that multiple infections increase virulence, here in terms of non-recovery and host castration. PMID:24892951

Effect of cortisol infusion patterns and castration on metabolic and immunological indices of stress response in cattle.

Science.gov (United States)

Ting, S T L; Earley, B; Crowe, M A

2004-05-01

This study tested the hypotheses that: (1) either acute stress induced by Burdizzo castration, or cortisol infusion would modulate plasma glucose, insulin and growth hormone (GH) concentrations; and (2) immune modulation induced by cortisol would be dependent on the pattern, intensity and duration of circulating cortisol concentrations. Fifty 9.2-month-old Holstein x Friesian bulls (232 +/- 2.0 kg) were blocked by weight and randomly assigned to one of five treatments (n = 10 per treatment): (1) sham handled control; (2) Burdizzo castration; (3) hydrocortisone infusion to mimic the castration-induced secretion pattern of cortisol; (4) hourly pulse infusion of hydrocortisone; and (5) sustained infusion of hydrocortisone for 8h. Blood samples were collected intensively on day 0, and weekly from days 1 to 35. Castration acutely increased plasma cortisol, GH and haptoglobin concentrations, suppressed lymphocyte in vitro interferon-gamma (IFN-gamma) production, but had no effect on plasma glucose and insulin concentrations. Cortisol infusion to simulate the castration-induced secretion pattern of cortisol, and pulse infusion of cortisol did not suppress the IFN-gamma production. A sustained infusion of cortisol resulted in the transient suppression of IFN-gamma production. Moreover, the sustained cortisol infusion resulted in increased plasma glucose, insulin and GH concentrations. The overall 14-day feed intakes and 35-day growth rates were not affected by treatments. In conclusion, cortisol infusion to induce immune suppression in vivo occurred only at pharmacological doses. Within physiological ranges, cortisol was not associated with the suppression of immune function, indicating that during castration cortisol per se is not responsible for the suppression of in vitro IFN-gamma production.

Prostate tumor-derived exosomes down-regulate NKG2D expression on natural killer cells and CD8+ T cells: mechanism of immune evasion.

Directory of Open Access Journals (Sweden)

Marie Lundholm

Full Text Available Tumor-derived exosomes, which are nanometer-sized extracellular vesicles of endosomal origin, have emerged as promoters of tumor immune evasion but their role in prostate cancer (PC progression is poorly understood. In this study, we investigated the ability of prostate tumor-derived exosomes to downregulate NKG2D expression on natural killer (NK and CD8+ T cells. NKG2D is an activating cytotoxicity receptor whose aberrant loss in cancer plays an important role in immune suppression. Using flow cytometry, we found that exosomes produced by human PC cells express ligands for NKG2D on their surface. The NKG2D ligand-expressing prostate tumor-derived exosomes selectively induced downregulation of NKG2D on NK and CD8+ T cells in a dose-dependent manner, leading to impaired cytotoxic function in vitro. Consistent with these findings, patients with castration-resistant PC (CRPC showed a significant decrease in surface NKG2D expression on circulating NK and CD8+ T cells compared to healthy individuals. Tumor-derived exosomes are likely involved in this NKG2D downregulation, since incubation of healthy lymphocytes with exosomes isolated from serum or plasma of CRPC patients triggered downregulation of NKG2D expression in effector lymphocytes. These data suggest prostate tumor-derived exosomes as down-regulators of the NKG2D-mediated cytotoxic response in PC patients, thus promoting immune suppression and tumor escape.

Modeling the effects of space structure and combination therapies on phenotypic heterogeneity and drug resistance in solid tumors.

Science.gov (United States)

Lorz, Alexander; Lorenzi, Tommaso; Clairambault, Jean; Escargueil, Alexandre; Perthame, Benoît

2015-01-01

Histopathological evidence supports the idea that the emergence of phenotypic heterogeneity and resistance to cytotoxic drugs can be considered as a process of selection in tumor cell populations. In this framework, can we explain intra-tumor heterogeneity in terms of selection driven by the local cell environment? Can we overcome the emergence of resistance and favor the eradication of cancer cells by using combination therapies? Bearing these questions in mind, we develop a model describing cell dynamics inside a tumor spheroid under the effects of cytotoxic and cytostatic drugs. Cancer cells are assumed to be structured as a population by two real variables standing for space position and the expression level of a phenotype of resistance to cytotoxic drugs. The model takes explicitly into account the dynamics of resources and anticancer drugs as well as their interactions with the cell population under treatment. We analyze the effects of space structure and combination therapies on phenotypic heterogeneity and chemotherapeutic resistance. Furthermore, we study the efficacy of combined therapy protocols based on constant infusion and bang-bang delivery of cytotoxic and cytostatic drugs.

{sup 177}Lu-PSMA-617 radioligand therapy and outcome in patients with metastasized castration-resistant prostate cancer

Energy Technology Data Exchange (ETDEWEB)

Braeuer, Axel; Grubert, Lena Sophie; Roll, Wolfgang; Schaefers, Michael; Rahbar, Kambiz [University Hospital Muenster, Department of Nuclear Medicine, Muenster (Germany); Schrader, Andres Jan; Boegemann, Martin [University Hospital Muenster, Department of Urology, Muenster (Germany)

2017-09-15

Radioligand therapies targeting prostate-specific membrane antigen (PSMA) have been established for the treatment of metastasized castration-resistant prostate cancer (mCRPC) in the last decade and show promising response rates and a favourable toxicity profile. The aim of this study was to evaluate the overall survival (OS) and to identify parameters predicting outcome in mCRPC patients treated with {sup 177}Lu-PSMA-617. Between December 2014 and January 2017, 59 consecutive patients (median age 72 years); interquartile range, (IQR, 66-76 years) with mCRPC, who had been treated with at least one next-generation antihormonal drug as well as chemotherapy, were included in this study. Biochemical response was evaluated using Prostate Cancer Working Group 3 (PCWG3) criteria. Survival was evaluated using Kaplan-Meier estimates and Cox regression proportional hazards model. Toxicity was assessed using Common Toxicity Criteria for Adverse Events (CTCAE). The study was approved by the local ethics committee. The 59 patients were treated with a total of 159 cycles (median 3 cycles, range 1-7) of {sup 177}Lu-PSMA-617 (median dose 6.11 GBq, IQR 5.9-6.3 GBq). The median follow-up was 24 weeks (IQR 15-36 weeks). Follow-up data for at least 12 weeks (PCWG3) were available in 76% (45) of the patients. For outcome results data from all patients treated with at least one cycle were analysed. A decline in prostate-specific antigen (PSA) of ≥50% occurred in 53%, and a decline in PSA of any amount in 91% of patients. The estimated median OS was 32 weeks. An initial alkaline phosphatase (ALP) level <220 U/L and a PSA decline after the first cycle were associated with a longer OS (56 vs. 28 weeks, p < 0.01, and 56 vs. 29 weeks, p = 0.04, respectively). The median estimated PSA progression-free survival (PPFS) was 18 weeks. Only ALP level <220 U/L was significantly associated with a longer PPFS (41 vs. 18 weeks, p < 0.01). A PSA decline after the first cycle of {sup 177}Lu-PSMA-617

Anaplasia and drug selection-independent overexpression of the multidrug resistance gene, MDR1, in Wilms' tumor.

Science.gov (United States)

Re, G G; Willingham, M C; el Bahtimi, R; Brownlee, N A; Hazen-Martin, D J; Garvin, A J

1997-02-01

One reason for the failure of chemotherapy is the overexpression of the multidrug resistance gene, MDR1. The product of this gene is the multidrug transporter P-glycoprotein, an ATP-dependent pump that extrudes drugs from the cytoplasm. Some tumors inherently express P-glycoprotein, whereas others acquire the ability to do so after exposure to certain chemotherapeutic agents, often by the mechanism of gene amplification. Classical Wilms' tumors (nephroblastoma) typically respond to therapy and have a good prognosis. On the contrary, anaplastic Wilms' tumors are generally refractory to chemotherapy. These anaplastic variants are rare (4.5% of all Wilms' tumors reported in the United States), aggressive, and often fatal forms of tumor, which are commonly thought to result from the progression of classical Wilms' tumors. To investigate the basis for this differential response to therapy, we examined a number of classical and anaplastic Wilms' tumors for the expression of the MDR1 gene by immunohistochemical and mRNA analysis. Classical Wilms' tumors consistently did not express P-glycoprotein except in areas of tubular differentiation, as in normal kidney. Similarly, two of three anaplastic tumors failed to show P-glycoprotein expression. In contrast, cultured cells derived from a third anaplastic tumor, W4, exhibited strong P-glycoprotein expression and were drug resistant in vitro. Southern analysis revealed that W4 cells contained a single copy of the MDR1 gene per haploid genome similar to normal cells, demonstrating that the overexpression of MDR1 was not caused by gene amplification. Transcriptional activation of the MDR1 gene would be in keeping with the concept that p53 might act as a transcriptional repressor of the MDR1 gene.

Prognostic factor analysis in patients with advanced prostate cancer treated by castration plus anandron or placebo: A final update

NARCIS (Netherlands)

de Reijke, Theo; Derobert, Eric

2002-01-01

Purpose: Different outcome results have been published in trials comparing maximal androgen blockade (MAB) with chemical or surgical castration alone. The conflicting results could be explained by the fact that patients were included with different prognostic factors. In this new analysis of the

The pluripotency factor Nanog is directly upregulated by the androgen receptor in prostate cancer cells.

Science.gov (United States)

Kregel, Steven; Szmulewitz, Russell Z; Vander Griend, Donald J

2014-11-01

The Androgen Receptor (AR) is a nuclear hormone receptor that functions as a critical oncogene in all stages of prostate cancer progression, including progression to castration-resistance following androgen-deprivation therapy. Thus, identifying and targeting critical AR-regulated genes is one potential method to block castration-resistant cancer proliferation. Of particular importance are transcription factors that regulate stem cell pluripotency; many of these genes are emerging as critical oncogenes in numerous tumor cell types. Of these, Nanog has been previously shown to increase the self-renewal and stem-like properties of prostate cancer cells. Thus, we hypothesized that Nanog is a candidate AR target gene that may impart castration-resistance. We modulated AR signaling in LNCaP prostate cancer cells and assayed for Nanog expression. Direct AR binding to the NANOG promoter was tested using AR Chromatin Immunoprecipation (ChIP) and analyses of publically available AR ChIP-sequencing data-sets. Nanog over-expressing cells were analyzed for cell growth and cytotoxicity in response to the AR antagonist enzalutamide and the microtubule stabilizing agent docetaxel. AR signaling upregulates Nanog mRNA and protein. AR binds directly to the NANOG promoter, and was not identified within 75 kb of the NANOGP8 pseudogene, suggesting the NANOG gene locus was preferentially activated. Nanog overexpression in LNCaP cells increases overall growth, but does not increase resistance to enzalutamide or docetaxel. Nanog is a novel oncogenic AR target gene in prostate cancer cells, and stable expression of Nanog increases proliferation and growth of prostate cancer cells, but not resistance to enzalutamide or docetaxel. © 2014 Wiley Periodicals, Inc.

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

Skeletal-related events significantly impact health-related quality of life in metastatic castration-resistant prostate cancer: data from PREVAIL and AFFIRM trials.

Science.gov (United States)

Saad, F; Ivanescu, C; Phung, D; Loriot, Y; Abhyankar, S; Beer, T M; Tombal, B; Holmstrom, S

2017-03-01

We investigated the impact of skeletal-related events (SREs) on health-related quality of life (HRQoL) in patients with metastatic castration-resistant prostate cancer (mCRPC) in phase III trials of enzalutamide versus placebo. Patients with mCRPC experiencing at least one SRE during AFFIRM and PREVAIL were assessed for trajectory-adjusted mean change in HRQoL by first SRE using Functional Assessment of Cancer Therapy-Prostate (FACT-P; AFFIRM, three domains, and PREVAIL, nine domains) and EQ-5D (PREVAIL) instruments. First SREs caused HRQoL deterioration in both trials. Spinal cord compression had the largest impact, with clinically meaningful reductions in seven of nine FACT-P domains in PREVAIL and all three in AFFIRM (mean (95% confidence interval (CI)) change in FACT-P total score -16.95 (-26.47, -7.44) and -9.69 (-16.10, -3.27), respectively). In PREVAIL, first SREs caused clinically meaningful declines in EQ-5D utility index, irrespective of category; spinal cord compression had the largest impact (mean (95% CI) change -0.24 (-0.39, -0.08)). In AFFIRM, FACT-P and FACT-General total scores showed clinically meaningful declines after radiation/surgery to bone. SREs were associated with clinically meaningful functional declines in the daily lives of patients with mCRPC. Spinal cord compression had the largest impact on HRQoL.

Noninvasive assessment of autonomic activity for evaluation of pain in calves, using surgical castration as a model.

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Stewart, M; Verkerk, G A; Stafford, K J; Schaefer, A L; Webster, J R

2010-08-01

The role of the autonomic nervous system (ANS) in mediating eye temperature responses during painful procedures was examined in thirty 4-mo-old bull calves randomly assigned to 4 treatments: 1) sham handling control (C; n=8), 2) surgical castration (SC; n=6), 3) local anesthesia with sham handling (LAC; n=8), and 4) local anesthesia with surgical castration (LASC; n=8). Maximum eye temperature ( degrees C), measured by infrared thermography, heart rate (HR), and heart rate variability (HRV) were recorded continuously from 25 min before to 20 min after castration. The HRV was analyzed by examining segments of 512 interbeat intervals before and after treatments and comparing the root mean square of successive differences (RMSSD), high and low frequency (HF and LF, respectively) power, and the ratio of LF and HF powers (LF:HF). Jugular blood samples were analyzed for norepinephrine and epinephrine in C and SC treatments and for cortisol during all treatments. There was an immediate increase in HR following castration in SC (+15.3+/-2.8 beats/min) and LASC (+6.3+/-2.4 beats/min) calves. Eye temperature increased during the 20-min observation period in SC and LASC calves (+0.47+/-0.05 degrees C and +0.28+/-0.05 degrees C, respectively), and there was a small increase in C calves (+0.10+/-0.05 degrees C). Following castration in SC calves, there was an increase in RMSSD (+25.8+/-6.4) and HF power (+11.0+/-6.5) and LF:HF decreased (-2.1+/-0.7). Following castration in LASC, there was an increase in RMSSD (+18.1+/-4.9) and a decrease in LF power (-10.2+/-5.0). Cortisol increased above baseline within 15 min following treatment in both castrated groups, but was greater for SC calves (+18.4+/-2.3 ng/mL) than for LASC calves (+11.1+/-1.9 ng/mL). After castration, norepinephrine increased 3-fold and epinephrine increased by half in SC calves but not in C calves. There were no changes in HR, HRV, or cortisol responses to C or LAC treatments. Local anesthetic reduced, but did

Live and carcass measurements of steers castrated at three different ...

African Journals Online (AJOL)

marbling, and fat thickness on the eye muscle between the three castrated groups. ... to compare the growth and development, feedlot performance and carcass .... is dependent upon the secretion of testosterone in the case of the bull. Thus ...

Effect of castration age on weight and size of some bones in Piemontese male cattle

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C. Lazzaroni

2010-04-01

Full Text Available Effect of pre- and post-pubertal castration on bone weight and measurements has been studied in 3 groups of Piemontese male cattle (EC - early castrated, LC - late castrated, IM - intact reared in the same environmental conditions and slaughtered at about 18 month of age, at about 550 kg of l.w., and at the same commercial fattening degree. At side commercial dissection all separated bones were weighted, and on the main ones (scapula, humerus, radius, femur, and tibia linear measures were recorded and then some conformation ratios were calculated (weight/length, length/width, and length/circumference. Data were analysed by GLM ANCOVA procedure, correcting data on side weight to avoid bias due to differences in carcass weight. No differences were found in side bone weight (23.58 ± 2.61 kg, so as in single bone weight, measures and ratios.

Budgetary Impact of Cabazitaxel Use After Docetaxel Treatment for Metastatic Castration-Resistant Prostate Cancer.

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Flannery, Kyle; Drea, Ed; Hudspeth, Louis; Corman, Shelby; Gao, Xin; Xue, Mei; Miao, Raymond

2017-04-01

With the approval of several new treatments for metastatic castration-resistant prostate cancer (mCRPC), budgetary impact is a concern for health plan decision makers. Budget impact models (BIMs) are becoming a requirement in many countries as part of formulary approval or reimbursement decisions. Cabazitaxel is a second-generation taxane developed to overcome resistance to docetaxel and is approved for the treatment of patients with mCRPC previously treated with a docetaxel-containing regimen. To estimate a 1-year projected budget impact of varying utilization rates of cabazitaxel as a second-line treatment for mCRPC following docetaxel, using a hypothetical U.S. private managed care plan with 1 million members. A BIM was developed to evaluate costs for currently available treatment options for patients with mCRPC previously treated with docetaxel. Treatments included in the model were cabazitaxel, abiraterone acetate, enzalutamide, and radium-223, with utilization rates derived from market research data. Medication costs were calculated according to published pricing benchmarks factored by dosing and duration of therapy as stated in the prescribing information for each agent. Published rates and costs of grade 3-4 adverse events were also factored into the model. In addition, the model reports budget impact under 2 scenarios. In the first base-case scenario, patient out-of-pocket costs were subtracted from the total cost of treatment. In the second scenario, all treatment costs were assumed to be paid by the plan. In a hypothetical 1 million-member health plan population, 100 patients were estimated to receive second-line treatment for mCRPC after treatment with docetaxel. Using current utilization rates for the 4 agents of interest, the base-case scenario estimated the cost of second-line treatment after docetaxel to be $6,331,704, or $0.528 per member per month (PMPM). In a scenario where cabazitaxel use increases from the base-rate case of 24% to a

Early Prediction of Therapy Response to Abiraterone Acetate Using PSA Subforms in Patients with Castration Resistant Prostate Cancer

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Katrin Schlack

2016-09-01

Full Text Available The purpose of this study was to evaluate the prognostic ability of early changes of total prostate specific antigen (tPSA, free PSA (fPSA, [−2]proPSA and the Prostate Health Index (PHI following initiation of Abiraterone-therapy in men with castration resistant prostate cancer (mCRPC. In 25 patients, PSA-subforms were analyzed before and at 8–12 weeks under therapy as prognosticators of progression-free-survival (PFS and overall survival (OS. Comparing patients with a PFS < vs. ≥12 months by using Mann–Whitney–Wilcoxon Tests, the relative-median-change of tPSA (−0.1% vs. −86.8%; p = 0.02, fPSA (12.1% vs. −55.3%; p = 0.03 and [−2]proPSA (8.1% vs. −59.3%; p = 0.05 differed significantly. For men with ≤ vs. >15 months of OS there was a non-significant trend for a difference in the relative-median-change of fPSA (17.0% vs. −46.3%; p = 0.06. In Kaplan–Meier analyses, declining fPSA and [−2]proPSA were associated with a longer median PFS (13 months, 95% confidence interval (CI: 9.6–16.4 vs. 10 months, 95% CI: 3.5–16.5; p = 0.11, respectively. Correspondingly, decreasing fPSA and [−2]proPSA values indicated an OS of 32 months (95% CI: not reached (NR compared to 21 months in men with rising values (95% CI: 7.7–34.3; p = 0.14, respectively. We concluded that the addition of fPSA- and [−2]proPSA-changes to tPSA-information might be further studied as potential markers of early Abiraterone response in mCRPC patients.

Characterization and drug resistance patterns of Ewing's sarcoma family tumor cell lines.

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William A May

Full Text Available Despite intensive treatment with chemotherapy, radiotherapy and surgery, over 70% of patients with metastatic Ewing's Sarcoma Family of Tumors (EFT will die of their disease. We hypothesize that properly characterized laboratory models reflecting the drug resistance of clinical tumors will facilitate the application of new therapeutic agents to EFT. To determine resistance patterns, we studied newly established EFT cell lines derived from different points in therapy: two established at diagnosis (CHLA-9, CHLA-32, two after chemotherapy and progressive disease (CHLA-10, CHLA-25, and two at relapse after myeloablative therapy and autologous bone marrow transplantation (post-ABMT (CHLA-258, COG-E-352. The new lines were compared to widely studied EFT lines TC-71, TC-32, SK-N-MC, and A-673. These lines were extensively characterized with regard to identity (short tandem repeat (STR analysis, p53, p16/14 status, and EWS/ETS breakpoint and target gene expression profile. The DIMSCAN cytotoxicity assay was used to assess in vitro drug sensitivity to standard chemotherapy agents. No association was found between drug resistance and the expression of EWS/ETS regulated genes in the EFT cell lines. No consistent association was observed between drug sensitivity and p53 functionality or between drug sensitivity and p16/14 functionality across the cell lines. Exposure to chemotherapy prior to cell line initiation correlated with drug resistance of EFT cell lines in 5/8 tested agents at clinically achievable concentrations (CAC or the lower tested concentration (LTC: (cyclophosphamide (as 4-HC and doxorubicin at CAC, etoposide, irinotecan (as SN-38 and melphalan at LTC; P<0.1 for one agent, and P<0.05 for four agents. This panel of well-characterized drug-sensitive and drug-resistant cell lines will facilitate in vitro preclinical testing of new agents for EFT.

Two's a crowd? Crowding effect in a parasitic castrator drives differences in reproductive resource allocation in single vs double infections.

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Fong, Caitlin R; Moron, Nancy A; Kuris, Armand M

2017-04-01

The 'crowding effect' is a result of competition by parasites within a host for finite resources. Typically, the severity of this effect increases with increasing numbers of parasites within a host and manifests in reduced body size and thus fitness. Evidence for the crowding effect is mixed - while some have found negative effects, others have found a positive effect of increased parasite load on parasite fitness. Parasites are consumers with diverse trophic strategies reflected in their life history traits. These distinctions are useful to predict the effects of crowding. We studied a parasitic castrator, a parasite that usurps host reproductive energy and renders the host sterile. Parasitic castrators typically occur as single infections within hosts. With multiple parasitic castrators, we expect strong competition and evidence of crowding. We directly assess the effect of crowding on reproductive success in a barnacle population infected by a unique parasitic castrator, Hemioniscus balani, an isopod parasite that infects and blocks reproduction of barnacles. We find (1) strong evidence of crowding in double infections, (2) increased frequency of double infections in larger barnacle hosts with more resources and (3) perfect compensation in egg production, supporting strong space limitation. Our results document that the effects of crowding are particularly severe for this parasitic castrator, and may be applicable to other castrators that are also resource or space limited.

Effects of castration and weaning conducted concurrently or consecutively on behaviour, blood traits and performance in beef calves.

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Lambertz, C; Farke-Röver, A; Moors, E; Gauly, M

2015-01-01

The objectives of this study were to evaluate the effects of Burdizzo castration and abrupt weaning on the behaviour, blood traits and performance of beef calves when weaning was conducted concurrently or consecutively to castration. In total, 64 male beef calves aged between 6 and 7 months were assigned to a 2×2 factorial design with the following treatment groups (n=16 animals per treatment): (1) castrated and concurrently weaned in week 0 (CAS-WEA); (2) castrated in week 0 and weaned in week 4 (CAS-CON); (3) bulls weaned in week 0 (BUL-WEA); and (4) bulls weaned in week 4 (BUL-CON). The behaviour of the calves was observed for 3 days following weaning. Blood was collected weekly from weeks 0 to 5 and analysed for the acute-phase protein haptoglobin, and neutrophil and lymphocyte percentages. BW was recorded weekly from weeks 0 to 7. Animals were slaughtered at 17 months and weight, dressing percentage and carcass classifications were recorded. On day 1 after weaning, the number of vocalizations (calls/10 min) was higher in BUL-WEA (7.2) and CAS-WEA (5.4) than in calves of CAS-CON (2.8) and BUL-CON (2.9) groups (Panimals spent 20% lying on day 1 after weaning compared with 40% in CAS-WEA and BUL-WEA calves (P0.05). WEA groups showed an increased average daily gain (ADG) during weeks 0 to 3 and a reduced ADG during 4 to 7 weeks in comparison with CON animals. At slaughter, bulls were about 80 kg heavier than castrates and had a superior dressing percentage and carcass classification (P>0.05). In conclusion, weaning had a greater effect on the number of vocalizations, standing/walking and lying behaviour and ADG compared with Burdizzo castration. In comparison with undertaking the procedures separately, concurrent castration and weaning neither affected behaviour and haematological parameters nor impaired performance. There was no evidence that the concurrent application of both treatments markedly increased the stress response compared with their application at

The PREVAIL trial of enzalutamide in men with chemotherapy-naïve, metastatic castration-resistant prostate cancer: Post hoc analysis of Korean patients.

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Kim, Choung-Soo; Theeuwes, Ad; Kwon, Dong Deuk; Choi, Young Deuk; Chung, Byung Ha; Lee, Hyun Moo; Lee, Kang Hyun; Lee, Sang Eun

2016-05-01

This post hoc analysis evaluated treatment effects, safety, and pharmacokinetics of enzalutamide in Korean patients in the phase 3, double-blind, placebo-controlled PREVAIL trial. Asymptomatic or mildly symptomatic chemotherapy-naive men with metastatic castration-resistant prostate cancer that progressed on androgen deprivation therapy received 160 mg/d oral enzalutamide or placebo (1:1) until death or discontinuation due to radiographic progression or skeletal-related event and initiation of subsequent therapy. Coprimary end points were centrally assessed radiographic progression-free survival (rPFS) and overall survival (OS). Secondary end points included investigator-assessed rPFS, time to initiation of chemotherapy, time to prostate-specific antigen (PSA) progression, PSA response (≥50% decline), and time to skeletal-related event. Of 1,717 total patients, 78 patients were enrolled in Korea (enzalutamide, n=40; placebo, n=38). Hazard ratios (95% confidence interval) for enzalutamide versus placebo were 0.23 (0.02-2.24) for centrally assessed rPFS, 0.77 (0.28-2.15) for OS, 0.21 (0.08-0.51) for time to chemotherapy, and 0.31 (0.17-0.56) for time to PSA progression. A PSA response was observed in 70.0% of enzalutamide-treated and 10.5% of placebo-treated Korean patients. Adverse events of grade ≥3 occurred in 33% of enzalutamide-treated and 11% of placebo-treated Korean patients, with median treatment durations of 13.0 and 5.1 months, respectively. At 13 weeks, the plasma concentration of enzalutamide plus N-desmethyl enzalutamide was similar in Korean and non-Korean patients (geometric mean ratio, 1.04; 90% confidence interval, 0.97-1.10). In Korean patients, treatment effects and safety of enzalutamide were consistent with those observed in the overall PREVAIL study population (ClinicalTrials.gov Identifier: NCT01212991).

177Lu-DKFZ-PSMA-617 therapy in metastatic castration resistant prostate cancer: safety, efficacy, and quality of life assessment

International Nuclear Information System (INIS)

Yadav, Madhav Prasad; Ballal, Sanjana; Tripathi, Madhavi; Damle, Nishikant Avinash; Bal, Chandrasekhar; Sahoo, Ranjit Kumar; Seth, Amlesh

2017-01-01

The purpose of this study was to evaluate the efficacy and safety of a novel theranostic agent, 177 Lu-DKFZ-PSMA-617 therapy in metastatic castration resistant prostate cancer (mCRPC). Thirty-one mCRPC patients with progressive disease despite second-line hormonal therapy and/or docetaxel chemotherapy were recruited for the study. All patients underwent diagnostic 68 Ga-PSMA-HBED-CCPET/CT, prior to inclusion for therapy. Included patients then underwent quarterly 177 Lu-DKFZ-PSMA-617 therapy. Hematological, kidney function, liver function tests, and serum PSA levels were recorded before and after therapy at 2 weeks, 4 weeks, and 3 month intervals. Biochemical response was assessed with trend in serum PSA levels. Metabolic response was assessed by PERCIST 1 criteria. Clinical response was assessed by visual analogue score (VASmax) analgesic score (AS), Karanofsky performance status (KPS), and toxicity and response criteria of the Eastern Cooperative Oncology Group (ECOG) criteria. The mean age of patients was 65.93 ± 9.77 years (range: 38-81 years). The mean activity administered in the 31 patients was 5069 ± 1845 MBq ranging from one to four cycles. There was a decline in the mean serum PSA levels from the baseline (baseline: 275 ng/mL, post 1st cycle therapy: 141.75 ng/mL). Based on biochemical response criteria 2/31, 20/31, 3/31, and 6/31 had complete response (CR), partial response(PR), stable disease (SD), and progressive disease (PD), respectively. Metabolic response revealed 2/6 patients with CR, and the remaining 3/6 patients with PR and 1/6 patients with SD. The mean VASmax score decreased from 7.5 to 3. The mean analgesic score decreased from 2.5 to 1.8 after therapy. The mean KPS score improved from 50.32 to 65.42 after therapies. The mean ECOG performance status improved from 2.54 to 1.78 after therapy. Two patients experienced grade I and grade II hemoglobin toxicity each. None of the patients experienced nephrotoxicity or hepatotoxicity. 177 Lu

Cancer stem cells and the tumor microenvironment: interplay in tumor heterogeneity.

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Albini, Adriana; Bruno, Antonino; Gallo, Cristina; Pajardi, Giorgio; Noonan, Douglas M; Dallaglio, Katiuscia

2015-01-01

Tumor cells able to recapitulate tumor heterogeneity have been tracked, isolated and characterized in different tumor types, and are commonly named Cancer Stem Cells or Cancer Initiating Cells (CSC/CIC). CSC/CIC are disseminated in the tumor mass and are resistant to anti-cancer therapies and adverse conditions. They are able to divide into another stem cell and a "proliferating" cancer cell. They appear to be responsible for disease recurrence and metastatic dissemination even after apparent eradication of the primary tumor. The modulation of CSC/CIC activities by the tumor microenvironment (TUMIC) is still poorly known. CSC/CIC may mutually interact with the TUMIC in a special and unique manner depending on the TUMIC cells or proteins encountered. The TUMIC consists of extracellular matrix components as well as cellular players among which endothelial, stromal and immune cells, providing and responding to signals to/from the CSC/CIC. This interplay can contribute to the mechanisms through which CSC/CIC may reside in a dormant state in a tissue for years, later giving rise to tumor recurrence or metastasis in patients. Different TUMIC components, including the connective tissue, can differentially activate CIC/CSC in different areas of a tumor and contribute to the generation of cancer heterogeneity. Here, we review possible networking activities between the different components of the tumor microenvironment and CSC/CIC, with a focus on its role in tumor heterogeneity and progression. We also summarize novel therapeutic options that could target both CSC/CIC and the microenvironment to elude resistance mechanisms activated by CSC/CIC, responsible for disease recurrence and metastases.

Effects of topical anaesthetic and buccal meloxicam on average daily gain, behaviour and inflammation of unweaned beef calves following surgical castration.

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Van der Saag, D; Lomax, S; Windsor, P A; Taylor, C; Thomson, P; Hall, E; White, P J

2018-02-26

Although the pain caused by castration of calves is a significant animal welfare issue for the beef industry, analgesia is not always used for this procedure, largely because of practical limitations associated with injectable forms of pain relief. Novel analgesic formulations have now been developed for livestock to allow topical and buccal administration, offering practical options to improve cattle welfare if shown to be effective. To assess the effects of topical anaesthetic (TA) and buccal meloxicam (BM) on average daily gain (ADG), behaviour and inflammation following surgical castration of beef calves, a total of 50 unweaned bull calves were randomly allocated to: (1) sham castration (SHAM, n=10); (2) surgical castration (C, n=10); (3) surgical castration with pre-operative buccal meloxicam (CBM, n=10); (4) surgical castration with post-operative topical anaesthetic (CTA, n=10); and (5) surgical castration with pre-operative buccal meloxicam and post-operative topical anaesthetic (CBMTA, n=10). Calves were recorded on video for 5 h following treatment and the frequency and duration of specific behaviours displayed by each animal was later observed for 5 min every hour (total of 25 min). Average daily gain was calculated 1, 2 and 6 days following treatment. Scrotal diameter measurements and photographs of wounds were collected from all castrated calves 1, 2 and 6 days following treatment to evaluate inflammation and wound healing. Infrared photographs were used to identify maximum scrotal temperature. Digital photographs were used to visually score wounds on a numerical rating scale of 1 to 5, with signs of inflammation increasing and signs of healing decreasing with progressive scores. Sham castration calves displayed significantly less, and C calves displayed significantly more foot stamps than all other calves (P=0.005). Observations on the duration of time that calves displayed a hypometric 'stiff gait' locomotion, indicated that SHAM calves tended to

Evaluation of learning curves for ovariohysterectomy of dogs and cats and castration of dogs.

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Freeman, Lynetta J; Ferguson, Nancy; Fellenstein, Carol; Johnson, Ron; Constable, Peter D

2017-08-01

OBJECTIVE To define learning curves for fourth-year veterinary students performing ovariohysterectomy procedures in dogs and cats and castration in dogs. DESIGN Retrospective study. SAMPLE 3,196 ovariohysterectomies or castrations performed in dogs and cats by 88 veterinary students during a spay-neuter surgery and animal shelter rotation (n = 3,056) or by 1 experienced general practitioner (n = 140). PROCEDURES Data collected from medical records included patient signalment, type and duration of procedure, and sequence (by date and time) of the procedure within a list of procedures of the same type generated for each student. For each procedure type, geometric mean surgery time and 95% confidence intervals were determined for each number of surgeries completed by ≥ 10 students. Median surgery times for the same procedure types were determined for the experienced practitioner. The learning curve for each procedure was modeled with nonlinear (3-factor exponential equation with a nonzero asymptote) and linear regression. For each procedure, the asymptote (optimal surgery time) for students was compared with the experienced practitioner's median surgery time. RESULTS 2,945 surgeries (mean, 33/student) performed by ≥ 10 students were analyzed. Surgery time decreased in a nonlinear manner as student experience increased for castration of adult or pediatric dogs and ovariohysterectomy of pediatric dogs and adult or pediatric cats. Surgery time decreased in a linear manner as experience increased for ovariohysterectomy of adult dogs. CONCLUSIONS AND CLINICAL RELEVANCE To the authors' knowledge, this was the first study to map surgery times for common surgical procedures consecutively performed by veterinary students. Results clearly indicated the value of repetition to improve surgical skills (as measured by surgery time) during a 3-week period.

Detection of T790M, the acquired resistance EGFR mutation, by tumor biopsy versus noninvasive blood-based analyses

Science.gov (United States)

Sundaresan, Tilak K.; Sequist, Lecia V.; Heymach, John V.; Riely, Gregory J.; Jänne, Pasi A.; Koch, Walter H.; Sullivan, James P.; Fox, Douglas B.; Maher, Robert; Muzikansky, Alona; Webb, Andrew; Tran, Hai T.; Giri, Uma; Fleisher, Martin; Yu, Helena A.; Wei, Wen; Johnson, Bruce E.; Barber, Thomas A.; Walsh, John R.; Engelman, Jeffrey A.; Stott, Shannon L.; Kapur, Ravi; Maheswaran, Shyamala; Toner, Mehmet

2015-01-01

Purpose The T790M gatekeeper mutation in the Epidermal Growth Factor Receptor (EGFR) is acquired by some EGFR-mutant non-small cell lung cancers (NSCLC) as they become resistant to selective tyrosine kinase inhibitors (TKIs). As third generation EGFR TKIs that overcome T790M-associated resistance become available, noninvasive approaches to T790M detection will become critical to guide management. Experimental Design As part of a multi-institutional Stand-Up-To-Cancer collaboration, we performed an exploratory analysis of 40 patients with EGFR-mutant tumors progressing on EGFR TKI therapy. We compared the T790M genotype from tumor biopsies with analysis of simultaneously collected circulating tumor cells (CTC) and circulating tumor DNA (ctDNA). Results T790M genotypes were successfully obtained in 30 (75%) tumor biopsies, 28 (70%) CTC samples and 32 (80%) ctDNA samples. The resistance-associated mutation was detected in 47–50% of patients using each of the genotyping assays, with concordance among them ranging from 57–74%. While CTC- and ctDNA-based genotyping were each unsuccessful in 20–30% of cases, the two assays together enabled genotyping in all patients with an available blood sample, and they identified the T790M mutation in 14 (35%) patients in whom the concurrent biopsy was negative or indeterminate. Conclusion Discordant genotypes between tumor biopsy and blood-based analyses may result from technological differences, as well as sampling different tumor cell populations. The use of complementary approaches may provide the most complete assessment of each patient’s cancer, which should be validated in predicting response to T790M-targeted inhibitors. PMID:26446944

Performance and nutritional evaluation of beef cattle raised on pasture, castrated at different ages, with and without supplementation

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Anilza Andréia da Rocha

2012-04-01

Full Text Available The objective of this study was to evaluate performance and nutritional traits of beef cattle raised on pastures, castrated at different ages, with and without supplementation. Forty-four crossbred young bulls with predominance of Zebu breed at initial average age of 120±30 days were used in the experiment. Animals were distributed in a completely randomized design in a factorial arrangement with four ages of castration and two supplementation systems. The animals were distributed into four groups and placed on Brachiaria decumbens Stapf pastures, where they were fed concentrate supplementation or mineral salt ad libtum (control. Animals were castrated at 120, 240 and 360 days of age with average body weight of 115, 175 and 276 kg, castrated or not, in each supplementation group. Concentrate supplement composition and the amount supplied to the animals varied according to the time of the year and development phase of the animals. Trials were carried out to evaluate nutritional variables in each of the following phases: suckling, growth in the dry season and growth in the dry/rainy transition season. Concentrate supplementation improved the use of pasture, although it may have caused substitutive effect in all seasons evaluated. Castration of the animals before the dry season impaired animal development until the following dry/rainy transition season, especially when carried out during weaning. Concentrate supply may reduce some effects of this stress.

DEspR roles in tumor vasculo-angiogenesis, invasiveness, CSC-survival and anoikis resistance: a 'common receptor coordinator' paradigm.

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Herrera, Victoria L; Decano, Julius L; Tan, Glaiza A; Moran, Ann M; Pasion, Khristine A; Matsubara, Yuichi; Ruiz-Opazo, Nelson

2014-01-01

A priori, a common receptor induced in tumor microvessels, cancer cells and cancer stem-like cells (CSCs) that is involved in tumor angiogenesis, invasiveness, and CSC anoikis resistance and survival, could underlie contemporaneous coordination of these events rather than assume stochasticity. Here we show that functional analysis of the dual endothelin1/VEGFsignal peptide receptor, DEspR, (formerly named Dear, Chr.4q31.2) supports the putative common receptor paradigm in pancreatic ductal adenocarcinoma (PDAC) and glioblastoma (GBM) selected for their invasiveness, CD133+CSCs, and polar angiogenic features. Unlike normal tissue, DEspR is detected in PDAC and GBM microvessels, tumor cells, and CSCs isolated from PDAC-Panc1 and GBM-U87 cells. DEspR-inhibition decreased angiogenesis, invasiveness, CSC-survival and anoikis resistance in vitro, and decreased Panc1-CSC and U87-CSC xenograft tumor growth, vasculo-angiogenesis and invasiveness in nude(nu/nu) rats, suggesting that DEspR activation would coordinate these tumor progression events. As an accessible, cell-surface 'common receptor coordinator', DEspR-inhibition defines a novel targeted-therapy paradigm for pancreatic cancer and glioblastoma.

Impact of Phosphoproteomics in the Era of Precision Medicine for Prostate Cancer

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Johnny R. Ramroop

2018-02-01

Full Text Available Prostate cancer is the most common malignancy in men in the United States. While androgen deprivation therapy results in tumor responses initially, there is relapse and progression to metastatic castration-resistant prostate cancer. Currently, all prostate cancer patients receive essentially the same treatment, and there is a need for clinically applicable technologies to provide predictive biomarkers toward personalized therapies. Genomic analyses of tumors are used for clinical applications, but with a paucity of obvious driver mutations in metastatic castration-resistant prostate cancer, other applications, such as phosphoproteomics, may complement this approach. Immunohistochemistry and reverse phase protein arrays are limited by the availability of reliable antibodies and evaluates a preselected number of targets. Mass spectrometry-based phosphoproteomics has been used to profile tumors consisting of thousands of phosphopeptides from individual patients after surgical resection or at autopsy. However, this approach is time consuming, and while a large number of candidate phosphopeptides are obtained for evaluation, limitations are reduced reproducibility, sensitivity, and precision. Targeted mass spectrometry can help eliminate these limitations and is more cost effective and less time consuming making it a practical platform for future clinical testing. In this review, we discuss the use of phosphoproteomics in prostate cancer and other clinical cancer tissues for target identification, hypothesis testing, and possible patient stratification. We highlight the majority of studies that have used phosphoproteomics in prostate cancer tissues and cell lines and propose ways forward to apply this approach in basic and clinical research. Overall, the implementation of phosphoproteomics via targeted mass spectrometry has tremendous potential to aid in the development of more rational, personalized therapies that will result in increased survival

A cyclopalladated complex interacts with mitochondrial membrane thiol-groups and induces the apoptotic intrinsic pathway in murine and cisplatin-resistant human tumor cells

International Nuclear Information System (INIS)

Serrano, Fabiana A; Machado, Joel Jr; Santos, Edson L; Pesquero, João B; Martins, Rafael M; Travassos, Luiz R; Caires, Antonio CF; Rodrigues, Elaine G; Matsuo, Alisson L; Monteforte, Priscila T; Bechara, Alexandre; Smaili, Soraya S; Santana, Débora P; Rodrigues, Tiago; Pereira, Felipe V; Silva, Luis S

2011-01-01

Systemic therapy for cancer metastatic lesions is difficult and generally renders a poor clinical response. Structural analogs of cisplatin, the most widely used synthetic metal complexes, show toxic side-effects and tumor cell resistance. Recently, palladium complexes with increased stability are being investigated to circumvent these limitations, and a biphosphinic cyclopalladated complex {Pd 2 [S (-) C 2 , N-dmpa] 2 (μ-dppe)Cl 2 } named C7a efficiently controls the subcutaneous development of B16F10-Nex2 murine melanoma in syngeneic mice. Presently, we investigated the melanoma cell killing mechanism induced by C7a, and extended preclinical studies. B16F10-Nex2 cells were treated in vitro with C7a in the presence/absence of DTT, and several parameters related to apoptosis induction were evaluated. Preclinical studies were performed, and mice were endovenously inoculated with B16F10-Nex2 cells, intraperitoneally treated with C7a, and lung metastatic nodules were counted. The cytotoxic effects and the respiratory metabolism were also determined in human tumor cell lines treated in vitro with C7a. Cyclopalladated complex interacts with thiol groups on the mitochondrial membrane proteins, causes dissipation of the mitochondrial membrane potential, and induces Bax translocation from the cytosol to mitochondria, colocalizing with a mitochondrial tracker. C7a also induced an increase in cytosolic calcium concentration, mainly from intracellular compartments, and a significant decrease in the ATP levels. Activation of effector caspases, chromatin condensation and DNA degradation, suggested that C7a activates the apoptotic intrinsic pathway in murine melanoma cells. In the preclinical studies, the C7a complex protected against murine metastatic melanoma and induced death in several human tumor cell lineages in vitro, including cisplatin-resistant ones. The mitochondria-dependent cell death was also induced by C7a in human tumor cells. The cyclopalladated C7a complex is

Attenuation of acute plasma cortisol response in calves following intravenous sodium salicylate administration prior to castration.

Science.gov (United States)

Coetzee, J F; Gehring, R; Bettenhausen, A C; Lubbers, B V; Toerber, S E; Thomson, D U; Kukanich, B; Apley, M D

2007-08-01

Pain associated with castration in cattle is an animal welfare concern in beef production. This study examined the effect of oral aspirin and intravenous (i.v.) sodium salicylate on acute plasma cortisol response following surgical castration. Twenty bulls, randomly assigned to the following groups, (i) uncastrated, untreated controls, (ii) castrated, untreated controls, (iii) 50 mg/kg sodium salicylate i.v. precastration and (iv) 50 mg/kg aspirin (acetylsalicylic acid) per os precastration, were blood sampled at 3, 10, 20, 30, 40, 50 min and 1, 1.5, 2, 4, 6, 8, 10 and 12 h postcastration. Samples were analyzed by competitive chemiluminescent immunoassay and fluorescence polarization immunoassay for cortisol and salicylate, respectively. Data were analyzed using noncompartmental analysis, a simple cosine model, anova and t-tests. Intravenous salicylate V(d(ss)) was 0.18 L/kg, Cl(B) was 3.36 mL/min/kg and t(1/2 lambda) was 0.63 h. Plasma salicylate concentrations above 25 microg/mL coincided with significant attenuation in peak cortisol concentrations (P = 0.029). Peak salicylate concentrations following oral aspirin administration was castrated groups was significantly higher than uncastrated controls (P = 0.018). These findings have implications for designing drug regimens to provide analgesia during routine animal husbandry procedures.

Preliminary study on the effect of castration and testosterone ...

African Journals Online (AJOL)

To study the effect of castration and testosterone replacement on the testosterone level of the New Zealand rabbit, 16 apparently healthy adult male rabbits were used. The animals were divided into four groups with each group having four rabbits. The first group served as the control group. The rabbits in the second group ...

"1"7"7Lu-PSMA-617 radioligand therapy and outcome in patients with metastasized castration-resistant prostate cancer

International Nuclear Information System (INIS)

Braeuer, Axel; Grubert, Lena Sophie; Roll, Wolfgang; Schaefers, Michael; Rahbar, Kambiz; Schrader, Andres Jan; Boegemann, Martin

2017-01-01

Radioligand therapies targeting prostate-specific membrane antigen (PSMA) have been established for the treatment of metastasized castration-resistant prostate cancer (mCRPC) in the last decade and show promising response rates and a favourable toxicity profile. The aim of this study was to evaluate the overall survival (OS) and to identify parameters predicting outcome in mCRPC patients treated with "1"7"7Lu-PSMA-617. Between December 2014 and January 2017, 59 consecutive patients (median age 72 years); interquartile range, (IQR, 66-76 years) with mCRPC, who had been treated with at least one next-generation antihormonal drug as well as chemotherapy, were included in this study. Biochemical response was evaluated using Prostate Cancer Working Group 3 (PCWG3) criteria. Survival was evaluated using Kaplan-Meier estimates and Cox regression proportional hazards model. Toxicity was assessed using Common Toxicity Criteria for Adverse Events (CTCAE). The study was approved by the local ethics committee. The 59 patients were treated with a total of 159 cycles (median 3 cycles, range 1-7) of "1"7"7Lu-PSMA-617 (median dose 6.11 GBq, IQR 5.9-6.3 GBq). The median follow-up was 24 weeks (IQR 15-36 weeks). Follow-up data for at least 12 weeks (PCWG3) were available in 76% (45) of the patients. For outcome results data from all patients treated with at least one cycle were analysed. A decline in prostate-specific antigen (PSA) of ≥50% occurred in 53%, and a decline in PSA of any amount in 91% of patients. The estimated median OS was 32 weeks. An initial alkaline phosphatase (ALP) level <220 U/L and a PSA decline after the first cycle were associated with a longer OS (56 vs. 28 weeks, p < 0.01, and 56 vs. 29 weeks, p = 0.04, respectively). The median estimated PSA progression-free survival (PPFS) was 18 weeks. Only ALP level <220 U/L was significantly associated with a longer PPFS (41 vs. 18 weeks, p < 0.01). A PSA decline after the first cycle of "1"7"7Lu-PSMA-617 and an

Paucity of PD-L1 expression in prostate cancer: innate and adaptive immune resistance.

Science.gov (United States)

Martin, A M; Nirschl, T R; Nirschl, C J; Francica, B J; Kochel, C M; van Bokhoven, A; Meeker, A K; Lucia, M S; Anders, R A; DeMarzo, A M; Drake, C G

2015-12-01

Primary prostate cancers are infiltrated with programmed death-1 (PD-1) expressing CD8+ T-cells. However, in early clinical trials, men with metastatic castrate-resistant prostate cancer did not respond to PD-1 blockade as a monotherapy. One explanation for this unresponsiveness could be that prostate tumors generally do not express programmed death ligand-1 (PD-L1), the primary ligand for PD-1. However, lack of PD-L1 expression in prostate cancer would be surprising, given that phosphatase and tensin homolog (PTEN) loss is relatively common in prostate cancer and several studies have shown that PTEN loss correlates with PD-L1 upregulation--constituting a mechanism of innate immune resistance. This study tested whether prostate cancer cells were capable of expressing PD-L1, and whether the rare PD-L1 expression that occurs in human specimens correlates with PTEN loss. Human prostate cancer cell lines were evaluated for PD-L1 expression and loss of PTEN by flow cytometry and western blotting, respectively. Immunohistochemical (IHC) staining for PTEN was correlated with PD-L1 IHC using a series of resected human prostate cancer samples. In vitro, many prostate cancer cell lines upregulated PD-L1 expression in response to inflammatory cytokines, consistent with adaptive immune resistance. In these cell lines, no association between PTEN loss and PD-L1 expression was apparent. In primary prostate tumors, PD-L1 expression was rare, and was not associated with PTEN loss. These studies show that some prostate cancer cell lines are capable of expressing PD-L1. However, in human prostate cancer, PTEN loss is not associated with PD-L1 expression, arguing against innate immune resistance as a mechanism that mitigates antitumor immune responses in this disease.

Targeting Autophagy in the Tumor Microenvironment: New Challenges and Opportunities for Regulating Tumor Immunity

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Bassam Janji

2018-04-01

Full Text Available Cancer cells evolve in the tumor microenvironment, which is now well established as an integral part of the tumor and a determinant player in cancer cell adaptation and resistance to anti-cancer therapies. Despite the remarkable and fairly rapid progress over the past two decades regarding our understanding of the role of the tumor microenvironment in cancer development, its precise contribution to cancer resistance is still fragmented. This is mainly related to the complexity of the “tumor ecosystem” and the diversity of the stromal cell types that constitute the tumor microenvironment. Emerging data indicate that several factors, such as hypoxic stress, activate a plethora of resistance mechanisms, including autophagy, in tumor cells. Hypoxia-induced autophagy in the tumor microenvironment also activates several tumor escape mechanisms, which effectively counteract anti-tumor immune responses mediated by natural killer and cytotoxic T lymphocytes. Therefore, strategies aiming at targeting autophagy in cancer cells in combination with other therapeutic strategies have inspired significant interest to overcome immunological tolerance and promote tumor regression. However, a number of obstacles still hamper the application of autophagy inhibitors in clinics. First, the lack of selectivity of the current pharmacological inhibitors of autophagy makes difficult to draw a clear statement about its effective contribution in cancer. Second, autophagy has been also described as an important mechanism in tumor cells involved in presentation of antigens to T cells. Third, there is a circumstantial evidence that autophagy activation in some innate immune cells may support the maturation of these cells, and it is required for their anti-tumor activity. In this review, we will address these aspects and discuss our current knowledge on the benefits and the drawbacks of targeting autophagy in the context of anti-tumor immunity. We believe that it is

An Evaluation of Pinhole Castration as an Alternative Technique for ...

African Journals Online (AJOL)

We evaluated pinhole castration as an alternative technique for dog population control in resource poor rural communities of Gulu, Northern Uganda. Through a campaign dubbed 'Big Fix Gulu', households in selected communities were mobilized using radio announcements, posters and school visits, to present dogs for ...

Expression of P-glycoprotein and multidrug resistance associated protein in Ehrlich ascites tumor cells after fractionated irradiation

DEFF Research Database (Denmark)

Nielsen, D; Maare, C; Eriksen, J

2001-01-01

PURPOSE: To characterize irradiated murine tumor cells with respect to drug resistance, drug kinetics, and ATPase activity, and to evaluate the possible role of P-glycoprotein (PGP) and murine multidrug resistance associated protein (Mrp1) in the drug-resistant phenotype of these cells. METHODS...... AND MATERIALS: Sensitive Ehrlich ascites tumor cells (EHR2) were in vitro exposed to fractionated irradiation (60 Gy). Western blot analysis was performed for determination of PGP and Mrp1, reverse transcriptase-polymerase chain reaction (RT-PCR) for determination of mdr1a + b mRNA, and semiquantitative RT......-PCR for Mrp1 mRNA. The clonogenic assay was applied to investigate sensitivity, whereas the steady-state drug accumulation of daunorubicin (DNR), 3H-vincristine (VCR), and 3H-etoposide (VP16) was measured by spectrofluorometry and scintillation counting, respectively. For determining of ATPase activity...

External validation and newly development of a nomogram to predict overall survival of abiraterone-treated, castration-resistant patients with metastatic prostate cancer

Directory of Open Access Journals (Sweden)

Yun-Jie Yang

2018-01-01

Full Text Available Abiraterone acetate is approved for the treatment of castration-resistant prostate cancer (CRPC; however, its effects vary. An accurate prediction model to identify patient groups that will benefit from abiraterone treatment is therefore urgently required. The Chi model exhibits a good profile for risk classification, although its utility for the chemotherapy-naive group is unclear. This study aimed to externally validate the Chi model and develop a new nomogram to predict overall survival (OS. We retrospectively analyzed a cohort of 110 patients. Patients were distributed among good-, intermediate-, and poor-risk groups, according to the Chi model. The good-, intermediate-, and poor-risk groups had a sample size of 59 (53.6%, 34 (30.9%, and 17 (15.5% in our dataset, and a median OS of 48.4, 29.1, and 10.5 months, respectively. The C-index of external validation of Chi model was 0.726. Univariate and multivariate analyses identified low hemoglobin concentrations (<110 g l−1, liver metastasis, and a short time interval from androgen deprivation therapy to abiraterone initiation (<36 months as predictors of OS. Accordingly, a new nomogram was developed with a C-index equal to 0.757 (95% CI, 0.678–0.836. In conclusion, the Chi model predicted the prognosis of abiraterone-treated, chemotherapy-naive patients with mCRPC, and we developed a new nomogram to predict the overall survival of this group of patients with less parameters.

Axl receptor tyrosine kinase is up-regulated in metformin resistant prostate cancer cells

Science.gov (United States)

Bansal, Nitu; Mishra, Prasun J.; Stein, Mark; DiPaola, Robert S.; Bertino, Joseph R.

2015-01-01

Recent epidemiological studies showed that metformin, a widely used anti-diabetic drug might prevent certain cancers. Metformin also has an anti-proliferative effect in preclinical studies of both hematologic malignancies as well as solid cancers and clinical studies testing metformin as an anti-cancer drug are in progress. However, all cancer types do not respond to metformin with the same effectiveness or acquire resistance. To understand the mechanism of acquired resistance and possibly its mechanism of action as an anti-proliferative agent, we developed metformin resistant LNCaP prostate cancer cells. Metformin resistant LNCaP cells had an increased proliferation rate, increased migration and invasion ability as compared to the parental cells, and expressed markers of epithelial-mesenchymal transition (EMT). A detailed gene expression microarray comparing the resistant cells to the wild type cells revealed that Edil2, Ereg, Axl, Anax2, CD44 and Anax3 were the top up-regulated genes and calbindin 2 and TPTE (transmembrane phosphatase with tensin homology) and IGF1R were down regulated. We focused on Axl, a receptor tyrosine kinase that has been shown to be up regulated in several drug resistance cancers. Here, we show that the metformin resistant cell line as well as castrate resistant cell lines that over express Axl were more resistant to metformin, as well as to taxotere compared to androgen sensitive LNCaP and CWR22 cells that do not overexpress Axl. Forced overexpression of Axl in LNCaP cells decreased metformin and taxotere sensitivity and knockdown of Axl in resistant cells increased sensitivity to these drugs. Inhibition of Axl activity by R428, a small molecule Axl kinase inhibitor, sensitized metformin resistant cells that overexpressed Axl to metformin. Inhibitors of Axl may enhance tumor responses to metformin and other chemotherapy in cancers that over express Axl. PMID:26036314

Experimental study of apoptosis in the prostate tissue following castration

Directory of Open Access Journals (Sweden)

Y Doustar

2008-02-01

Full Text Available The Prostate gland is one of the accessory reproductive glands with important physiological functions necessary for successful reproduction. This gland depends on the presence of sex hormones including androgens for its natural function and normal growth and development. So in the case of hyperplasia, hypertrophy or other prostatic disease the most successful and efficient method of treatment is androgenic control that in some cases is unavoidable. The purpose of this study was to investigate the effects of androgenic depletion states by means of castration on the induction of apoptosis in the epithelial glandular cells of the prostate tissue. Two groups of male dogs each containing 5 animals per group were used in this study. The dogs were under observation for 1 month to detect any possible diseases or disorders. After this period the dogs in the treatment group underwent open castration to decrease the levels of the androgenic hormones in the blood while the dogs in the control group were left intact. One week after surgery, the prostate glands of control and treatment animals were collected and used to prepare microscopic sections. The sections were evaluated following staining with TUNEL (TerminaldeoxyNucleotidyl (dUTP transferase-mediated End Labeling and H&E methods. The Mann – Whitney U test was used for statistical analysis. Histopathological studies in the treatment group revealed the presence of various forms of apoptotic cells in the glandular epithelium. Average number of apoptotic cells in ten microscopic fields were significantly higher in the treatment group compared with the control group (p

RKIP inhibition in cervical cancer is associated with higher tumor aggressive behavior and resistance to cisplatin therapy.

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Olga Martinho

Full Text Available Cervical cancer is one of the most common cancers in women worldwide, being high-risk group the HPV infected, the leading etiological factor. The raf kinase inhibitory protein (RKIP has been associated with tumor progression and metastasis in several human neoplasms, however its role on cervical cancer is unclear. In the present study, 259 uterine cervix tissues, including cervicitis, cervical intraepithelial lesions and carcinomas, were analyzed for RKIP expression by immunohistochemistry. We found that RKIP expression was significantly decreased during malignant progression, being highly expressed in non-neoplastic tissues (54% of the samples; 73/135, and expressed at low levels in the cervix invasive carcinomas (∼15% (19/124. Following in vitro downregulation of RKIP, we observed a viability and proliferative advantage of RKIP-inhibited cells over time, which was associated with an altered cell cycle distribution and higher colony number in a colony formation assay. An in vitro wound healing assay showed that RKIP abrogation is associated with increased migratory capability. RKIP downregulation was also associated with an increased vascularization of the tumors in vivo using a CAM assay. Furthermore, RKIP inhibition induced cervical cancer cells apoptotic resistance to cisplatin treatment. In conclusion, we described that RKIP protein is significantly depleted during the malignant progression of cervical tumors. Despite the lack of association with patient clinical outcome, we demonstrate, in vitro and in vivo, that loss of RKIP expression can be one of the factors that are behind the aggressiveness, malignant progression and chemotherapy resistance of cervical cancer.

Impact of body composition parameters on clinical outcomes in patients with metastatic castrate-resistant prostate cancer treated with docetaxel.

Science.gov (United States)

Cushen, Samantha J; Power, Derek G; Murphy, Kevin P; McDermott, Ray; Griffin, Brendan T; Lim, Marvin; Daly, Louise; MacEneaney, Peter; O' Sullivan, Kathleen; Prado, Carla M; Ryan, Aoife M

2016-06-01

Body composition may influence clinical outcomes of certain chemotherapeutic agents. We examined the prognostic significance of skeletal muscle mass and adipose tissue on docetaxel toxicity and overall survival in patients with metastatic castrate resistant prostate cancer (mCRPC). A retrospective review of patients medical records with mCRPC, treated with docetaxel was conducted. Body composition parameters (skeletal muscle mass, muscle attenuation [MA], visceral and subcutaneous adipose tissue) were measured at L3 by computed tomography (CT) and defined using previously established cut points. Toxicity profile was assessed after 3 cycles of the drug and graded according to the National Cancer Institute Common Toxicity Criteria (version 4). Overall survival was analysed. Overall 63 patients, mean age 69 years (SD 8.3), were included. Sarcopenia was present in 47% (n = 30) and of these 26.7% (8/30) were sarcopenic obese. Common toxicities (all grades) observed included fatigue (80.9%), pain (46%), and constipation (34.9%). DLT occurred in 22 (34.9%) patients; of these 10 patients (15.8%) experienced dose reductions and 12 patients (19%) experienced dose terminations. Measurements of adiposity were not predictive of DLT, however 59.1% patients who had a combination of both sarcopenia and low MA experienced DLT compared to 29.3% of patients without sarcopenia and low MA (p = 0.021). Skeletal muscle index and MA were significantly lower in patients who experienced neutropenia (grade I-II) (46.5 cm 2 /m 2 vs. 51.2 cm 2 /m 2 , p = 0.005) compared to their counterparts (24.6 HU vs. 32.2 HU, p = 0.044). Neither sarcopenia nor sarcopenic obesity was associated with overall survival. In multivariate analysis, BMI ≥25 kg/m 2 (HR: 0.349, CI: 0.156-0.782, p = 0.010) was a significant predictor of longer overall survival and both visceral fat index ≥ median 58.7 cm 2 /m 2 (HR: 2.266 CI: 1.066-4.814, p = 0.033) and anaemia (HR: 2.81, CI: 1.297-6.091, p

{sup 177}Lu-DKFZ-PSMA-617 therapy in metastatic castration resistant prostate cancer: safety, efficacy, and quality of life assessment

Energy Technology Data Exchange (ETDEWEB)

Yadav, Madhav Prasad; Ballal, Sanjana; Tripathi, Madhavi; Damle, Nishikant Avinash; Bal, Chandrasekhar [All India Institute of Medical Sciences, Department of Nuclear Medicine, Ansari Nagar, New Delhi (India); Sahoo, Ranjit Kumar [All India Institute of Medical Sciences, Department of Medical Oncology, BR Ambedkar Rotary Cancer Hospital, New Delhi (India); Seth, Amlesh [All India Institute of Medical Sciences, Department of Urology, New Delhi (India)