Prostate Cancer

Nelson, William G.; Marzo, Angelo M. De; Isaacs, William B.

doi:10.1056/nejmra021562

Cited by 974 publications

(752 citation statements)

References 151 publications

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“…Researchers have hypothesized that CaP behaves heterogeneously and potentially aggressively due to numerous genetic or epigenetic alterations potentially identifiable long before they become clinically significant [28][29][30]. The molecular basis of alterations in nuclear structure that determine clinical risk for disease recurrence and progression to distant metastasis appear to be an important factor in these events.…”

Section: Discussionmentioning

confidence: 99%

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Using nuclear morphometry to predict the need for treatment among men with low grade, low stage prostate cancer enrolled in a program of expectant management with curative intent

Makarov¹,

Marlow²,

Epstein

et al. 2007

The Prostate

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PURPOSE-We assessed the use of quantitative clinical and pathologic information to predict which patients would eventually require treatment for prostate cancer (CaP) in an expectant management (EM) cohort.EXPERIMENTAL DESIGN-We identified 75 men having prostate cancer with favorable initial biopsy characteristics; 30 developed an unfavorable biopsy (Gleason grade >6, >2 cores with cancer, >50% of a core with cancer, or a palpable nodule) requiring treatment and 45 maintained favorable biopsies throughout a median follow-up of 2.7years. Demographic, clinical data and quantitative tissue histomorphometry determined by digital image analysis were analyzed.RESULTS-Logistic regression (LR) modeling generated a quantitative nuclear grade (QNG) signature based on the enrollment biopsy for differentiation of Favorable and Unfavorable groups using a variable LR selection criteria of P z < 0.05. The QNG signature utilized 12 nuclear morphometric descriptors (NMDs) and had an area under the receiver operator characteristic curve (ROC-AUC) of 87% with a sensitivity of 82%, specificity of 70% and accuracy of 75%. A multivariable LR model combining QNG signature with clinical and pathological variables yielded an AUC-ROC of 88% and a sensitivity of 81%, specificity of 78% and accuracy of 79%. A LR model using prostate volume, PSA density, and number of pre-diagnosis biopsies resulted in an AUC-ROC of 68% and a sensitivity of 85%, specificity of 37% and accuracy of 56%.CONCLUSIONS-QNG using EM prostate biopsies improves the predictive accuracy of LR models based on traditional clinicopathologic variables in determining which patients will ultimately develop an unfavorable biopsy. Our QNG-based model must be rigorously, prospectively validated prior to use in the clinical arena.Keywords prostate cancer; expectant management; quantitative nuclear grade; prostate biopsy; low grade and low stage cancer

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Section: Discussionmentioning

confidence: 99%

“…Such analysis may prevent unnecessary treatment of men with indolent CaP. Continued improvements in our model may be possible with addition of new biomarkers [28][29][30]. While this QNG model provides insight into the natural history of low volume CaP, it must be rigorously and prospectively validated prior to use in a clinical arena.…”

Section: Discussionmentioning

confidence: 99%

Using nuclear morphometry to predict the need for treatment among men with low grade, low stage prostate cancer enrolled in a program of expectant management with curative intent

Makarov¹,

Marlow²,

Epstein

et al. 2007

The Prostate

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“…1,2 Hormonal therapy is usually the first line of defense for CaP treatment by using drugs that lead to chemical castration, suppression of testosterone and dihydrotestosterone (DHT) biosynthesis. 3,4 The hormonal ablation approach has been achieved successfully using agonist (through desensitization) or antagonist analogue drugs, of the native Gonadotropin Releasing Hormone (GnRH).…”

Section: Introductionmentioning

confidence: 99%

GnRH-Gemcitabine Conjugates for the Treatment of Androgen-Independent Prostate Cancer: Pharmacokinetic Enhancements Combined with Targeted Drug Delivery

Καράμπελας

Argyros

Sayyad³

et al. 2014

Bioconjugate Chem.

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Gemcitabine, a drug with established efficacy against a number of solid tumors, has therapeutic limitations due to its rapid metabolic inactivation. The aim of this study was the development of an innovative strategy to produce a metabolically stable analogue of gemcitabine that could also be selectively delivered to prostate cancer (CaP) cells based on cell surface expression of the Gonadotropin Releasing HormoneReceptor (GnRH-R). The synthesis and evaluation of conjugated molecules, consisting of gemcitabine linked to a GnRH agonist, is presented along with results in androgen-independent prostate cancer models. NMR and ligand binding assays were employed to verify conservation of microenvironments responsible for binding of novel GnRH-gemcitabine conjugates to the GnRH-R. In vitro cytotoxicity, cellular uptake and metabolite formation of the conjugates were examined in CaP cell lines. Selected conjugates were efficacious in the in vitro assays with one of them, namely GSG, displaying high antiproliferative activity in CaP cell lines along with significant metabolic and pharmacokinetic advantages in comparison to gemcitabine. Finally, treatment of GnRH-R positive xenografted mice with GSG, showed a significant advantage in tumor growth inhibition when compared to gemcitabine. 3 IntroductionDespite advancements in methods for early cancer detection and improved insights into the molecular mechanisms and treatment options, advanced prostate cancer (CaP) remains a major health problem for the aging man. 1,2 Hormonal therapy is usually the first line of defense for CaP treatment by using drugs that lead to chemical castration, suppression of testosterone and dihydrotestosterone (DHT) biosynthesis. 3,4 The hormonal ablation approach has been achieved successfully using agonist (through desensitization) or antagonist analogue drugs, of the native Gonadotropin Releasing Hormone (GnRH). These drugs exert their effects primarily on the pituitary gland through the GnRH-R by lowering gonadotropins and downstream gonadal sex steroids. Nevertheless, in many cases after treatment, following initial tumor regression, CaP progresses to an androgen-independent state with poor prognosis, which presents a major challenge for the physician and the patient. 3,[5][6][7][8][9][10] Research on the GnRH-R has shown that its expression is not confined solely to the pituitary but that is also present in several other tissues such as prostate, breast 11-13 and the GnRH-R level of expression along with cell context is critical for cell responses to either agonist or antagonist drugs of the receptor. 14 It is also well established that GnRH-R gene expression is upregulated in patients with androgenindependent CaP, making the GnRH-R an attractive target for the design of novel and specific therapeutics. 15 A modern approach to improve conventional chemotherapy is by direct targeting of chemotherapeutic agents to cancer cells in order to enhance the tumoricidal effect and reduce peripheral toxicity of a specific drug. Linking chemo...

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“…Recently, we have isolated and purified from silymarin seven distinct flavonolignans namely silybin A, silybin B, isosilybin A, isosilybin B, silydianin, silychristin, isosilychristin and one flavonoid taxifolin ; and assessed their biological effects on many antiproliferative end points in human PCA cell lines (Davis-Searles et al, 2005). Isosilybin B ranked the most potent flavonolignan for nearly all end points including inhibition of prostate-specific antigen (PSA) secretion (Davis-Searles et al, 2005), which is used as a clinical tool in screening, diagnosis and treatment decisions for human PCA (Nelson et al, 2003). Here we conducted detailed mechanistic studies with isosilybin B focusing on AR by employing androgen-dependent LNCaP cells with single AR mutation (T877A), LAPC4 cells with wild-type AR and androgen-independent 22Rv1 cells with mutated AR (H874Y), though all the three cell lines have functional AR (Nagabhushan et al, 1996;Klein et al, 1997;Mendoza et al, 2002;Bernard et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Isosilybin B causes androgen receptor degradation in human prostate carcinoma cells via PI3K-Akt-Mdm2-mediated pathway

et al. 2008

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The identification and development of novel nontoxic phytochemicals that target androgen and androgen receptor (AR) signaling remains a priority for prostate cancer (PCA) control. In the present study, we assessed the antiandrogenic efficacy of isosilybin B employing human PCA LNCaP (mutated AR), 22Rv1 (mutated AR) and LAPC4 (wild-type AR) cells. Isosilybin B (10-90 lM) treatment decreased the AR and prostate specific antigen (PSA) levels in LNCaP, 22Rv1 and LAPC4 cells, but not in non-neoplastic human prostate epithelial PWR-1E cells. Isosilybin B treatment also inhibited synthetic androgen R1881-induced nuclear localization of AR, PSA expression and cell growth, and caused G 1 arrest. In mechanistic studies identifying AR degradation, isosilybin B caused increased phosphorylation of Akt (Ser-473 and Thr-308) and Mdm2 (Ser-166), which was linked with AR degradation as pretreatment with PI3K inhibitor (LY294002)-restored AR level. Further, overexpression of kinase-dead Akt largely reversed isosilybin B mediated-AR degradation suggesting a critical role of Akt in AR degradation. Antibody pull-down results also indicated that isosilybin B treatment enhances the formation of complex between Akt, Mdm2 and AR, which promotes phosphorylation-dependent AR ubiquitination and its degradation by proteasome. Together, present findings identify a novel mechanism for isosilybin B-mediated anticancer effects in human PCA cells.

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Prostate Cancer

Cited by 974 publications

References 151 publications

Using nuclear morphometry to predict the need for treatment among men with low grade, low stage prostate cancer enrolled in a program of expectant management with curative intent

Using nuclear morphometry to predict the need for treatment among men with low grade, low stage prostate cancer enrolled in a program of expectant management with curative intent

GnRH-Gemcitabine Conjugates for the Treatment of Androgen-Independent Prostate Cancer: Pharmacokinetic Enhancements Combined with Targeted Drug Delivery

Isosilybin B causes androgen receptor degradation in human prostate carcinoma cells via PI3K-Akt-Mdm2-mediated pathway

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