Publications by authors named "Rosalie Nolley"

40 Publications

Darinaparsin: solid tumor hypoxic cytotoxin and radiosensitizer.

Clin Cancer Res 2012 Jun 25;18(12):3366-76. Epub 2012 Apr 25.

Department of Radiation Oncology and Urology, School of Medicine, Stanford University, Stanford, California 94305, USA.

Purpose: Hypoxia is an important characteristic of the solid tumor microenvironment and constitutes a barrier for effective radiotherapy. Here, we studied the effects of darinaparsin (an arsenic cytotoxin) on survival and radiosensitivity of tumor cells in vitro under normoxia and hypoxia and in vivo using xenograft models, compared to effects on normal tissues.

Experimental Design: The cytotoxicity and radiosensitization of darinaparsin were first tested in vitro in a variety of solid tumor cell lines under both normoxia and hypoxia and compared with arsenic trioxide (ATO, an arsenical with reported cytotoxic and radiosensitizing activities on tumor cells). The effects were then tested in mouse models of xenograft tumors derived from tumor cell lines and clinical tumor specimens. The potential mechanisms of darinaparsin effects, including reactive oxygen species (ROS) generation, cellular damage, and changes in global gene expression, were also investigated.

Results: In comparison with ATO, darinaparsin had significantly higher in vitro cytotoxic and radiosensitizing activities against solid tumor cells under both normoxia and hypoxia. In vivo experiments confirmed these activities at doses that had no systemic toxicities. Importantly, darinaparsin did not radiosensitize normal bone marrow and actually radioprotected normal intestinal crypts. The darinaparsin-mediated antitumor effects under hypoxia were not dependent on ROS generation and oxidative damage, but were associated with inhibition of oncogene (RAS and MYC)-dependent gene expression.

Conclusion: Darinaparsin has significant and preferential cytotoxic and radiosensitizing effects on solid tumors as compared with normal cells. Darinaparsin may therefore increase the therapeutic index of radiation therapy and has near term translational potential.
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http://dx.doi.org/10.1158/1078-0432.CCR-11-3179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5518752PMC
June 2012

Length of site-specific positive surgical margins as a risk factor for biochemical recurrence following radical prostatectomy.

Int J Urol 2011 Apr 22;18(4):272-9. Epub 2011 Feb 22.

Department of Urology, Stanford University Medical Center, Stanford, California, USA.

Objectives: Positive surgical margins (PSM) have been associated with biochemical recurrence (BCR) after radical prostatectomy, but the significance of PSM length and location are debated. We assessed the impact of PSM lengths at specific locations for BCR in an open radical prostatectomy series.

Methods: Detailed clinical and pathological data were collected from 117 post-prostatectomy patients with PSM from 1984 to 2004 at our institution. PSM locations were classified as apex, mid-gland, base, bladder neck, and anterior fibromuscular region with lengths measured at each site. Aggregate PSM length was obtained by summing lengths of all PSM areas in contact with the inked surface. BCR was defined as serum prostate specific antigen level 0.2 ng/mL or greater. Cox proportional hazards regression analyses of PSM lengths were conducted either as a continuous or categorical variable relative to location as a predictor of BCR.

Results: Multivariate analyses demonstrated that as a continuous variable, PSM length at the anterior fibromuscular region (Hazard ratio [HR] = 1.17; P = 0.027) and bladder neck (HR = 1.29; P = 0.046) were significant predictors for BCR. As a categorical variable, PSM length ≥ 2 mm at the anterior fibromuscular area was significant for BCR (HR = 3.02; P = 0.036). Increasing Gleason grade and positive lymph node status were also found to be significant independent predictors for BCR.

Conclusion: PSM length at the anterior fibromuscular region (continuous and categorical) and the bladder neck (continuous) was significantly associated with BCR. Site-specific PSM length, along with Gleason grade and lymph node status, can be predictive of BCR and assist in risk stratification of patients with PSM following radical prostatectomy.
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http://dx.doi.org/10.1111/j.1442-2042.2011.02729.xDOI Listing
April 2011

Serum Mac-2BP does not distinguish men with high grade, large volume prostate cancer from men with benign prostatic hyperplasia.

Prostate 2011 Jan;71(1):26-31

Department of Urology, Stanford University School of Medicine, Stanford, California 94041, USA.

Background: Mac-2 binding protein (Mac-2BP) is a secreted protein that has been used as a serum prognostic marker for several types of cancers. A previous study showed that serum Mac-2BP was significantly higher (∼2-fold) in men with prostate cancer compared to healthy men. We investigated whether serum Mac-2BP could distinguish men with high grade, large volume prostate cancer from men with benign prostatic hyperplasia (BPH).

Methods: A commercially available ELISA kit was used to measure Mac-2BP in paired pre- and post-prostatectomy sera from 10 men with high grade, large volume prostate cancer, in pre-operative sera from 50 untreated men with high grade, large volume prostate cancer, and in sera from 50 men with clinical symptoms of BPH and biopsy-negative for prostate cancer. Results were analyzed by Student's t-test and receiver operating characteristic (ROC) curves.

Results: Levels of Mac-2BP did not decrease in post-prostatectomy sera, and Mac-2BP values were not significantly different in the sera of men with prostate cancer versus those with BPH.

Conclusion: Serum Mac-2BP does not appear to originate in the prostate and it is unlikely that Mac-2BP can be used for the differential diagnosis of prostate cancer versus BPH.
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http://dx.doi.org/10.1002/pros.21218DOI Listing
January 2011

Tissue slice grafts: an in vivo model of human prostate androgen signaling.

Am J Pathol 2010 Jul 14;177(1):229-39. Epub 2010 May 14.

Department of Urology, Stanford University School of Medicine, Stanford, CA 94305-5118, USA.

We developed a tissue slice graft (TSG) model by implanting thin, precision-cut tissue slices derived from fresh primary prostatic adenocarcinomas under the renal capsule of immunodeficient mice. This new in vivo model not only allows analysis of approximately all of the cell types present in prostate cancer within an intact tissue microenvironment, but also provides a more accurate assessment of the effects of interventions when tissues from the same specimen with similar cell composition and histology are used as control and experimental samples. The thinness of the slices ensures that sufficient samples can be obtained for large experiments as well as permits optimal exchange of nutrients, oxygen, and drugs between the grafted tissue and the host. Both benign and cancer tissues displayed characteristic histology and expression of cell-type specific markers for up to 3 months. Moreover, androgen-regulated protein expression diminished in TSGs after androgen ablation of the host and was restored after androgen repletion. Finally, many normal secretory epithelial cells and cancer cells in TSGs remained viable 2 months after androgen ablation, consistent with similar observations in postprostatectomy specimens following neoadjuvant androgen ablation. Among these were putative Nkx3.1(+) stem cells. Our novel TSG model has the appropriate characteristics to serve as a useful tool to model all stages of disease, including normal tissue, premalignant lesions, well-differentiated cancer, and poorly differentiated cancer.
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http://dx.doi.org/10.2353/ajpath.2010.090821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2893666PMC
July 2010

The significance of monoamine oxidase-A expression in high grade prostate cancer.

J Urol 2008 Nov 20;180(5):2206-11. Epub 2008 Sep 20.

Department of Urology, Stanford University School of Medicine, Stanford, California, USA.

Purpose: Gleason grade 4/5 prostate cancer is a determinant for recurrence following radical prostatectomy. Monoamine oxidase-A is over expressed in grade 4/5 compared to grade 3 cancer. Monoamine oxidase-A is also expressed by normal basal cells and in vitro studies suggest that its function is to repress secretory differentiation. Therefore, monoamine oxidase-A in grade 4/5 cancer might reflect dedifferentiation to a basal cell-like phenotype. We investigated whether monoamine oxidase-A expression correlates with another basal cell protein, CD44, in high grade cancer and whether either is associated with an aggressive phenotype.

Materials And Methods: A total of 133 grade 4/5 archival cancers from a cohort previously used to evaluate the prognostic significance of histomorphological variables were scored for monoamine oxidase-A and CD44 immunohistochemical labeling. Spearman rank correlations of the proteins, and histomorphological and clinical variables were determined. The univariate and multivariate value of each variable as a determinant of biochemical recurrence was assessed by logistic regression.

Results: Monoamine oxidase-A expression correlated with CD44. Neither was prognostic for biochemical recurrence. However, monoamine oxidase-A expression positively correlated with preoperative serum prostate specific antigen and the percent of grade 4/5 cancer.

Conclusions: Concurrent expression of monoamine oxidase-A and CD44 suggests that grade 4/5 cancer may be basal cell-like in nature, despite the absence of other classic basal cell biomarkers such as cytokeratins 5 and 14, and p63. The correlation of monoamine oxidase-A expression with prostate specific antigen and the percent of grade 4/5 cancer suggests that monoamine oxidase-A may contribute to growth of high grade cancer and that antidepressant drugs that target monoamine oxidase-A may have applications in treating prostate cancer.
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http://dx.doi.org/10.1016/j.juro.2008.07.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2743604PMC
November 2008

Inhibition of monoamine oxidase A promotes secretory differentiation in basal prostatic epithelial cells.

Differentiation 2008 Sep 31;76(7):820-30. Epub 2008 Jan 31.

Department of Urology Stanford University School of Medicine 300 Pasteur Drive, Grant Building S227 MC 5118, Stanford, CA 94305, USA.

Monoamine oxidase A (MAO-A) expression is associated with high-grade prostate cancer. Immunohistochemistry showed that MAO-A is also expressed in the basal epithelial cells of normal prostate glands. Using cultured primary prostatic epithelial cells as a model, we showed that MAO-A prevents basal epithelial cells from differentiating into secretory cells. Under differentiation-promoting conditions, clorgyline, an irreversible MAO-A inhibitor, induced secretory cell-like morphology and repressed expression of cytokeratin 14, a basal cell marker. More importantly, clorgyline induced mRNA and protein expression of androgen receptor (AR), a hallmark of secretory epithelial cells. In clorgyline-treated cells, androgen induced luciferase activity controlled by the promoter of prostate-specific antigen, an AR target gene, in a dose-dependent manner. This activity was blocked by the AR antagonist Casodex, showing that AR is functional. In turn, androgen decreased MAO-A expression in clorgyline-treated, secretory-like cells. Our results demonstrated that cultured basal epithelial cells have the potential to differentiate into secretory cells, and that inhibition of MAO-A is a key factor in promoting this process. Increased expression of MAO-A in high-grade prostate cancer may be an important contributor to its de-differentiated phenotype, raising the possibility that MAO-A inhibition may restore differentiation and reverse the aggressive behavior of high-grade cancer.
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http://dx.doi.org/10.1111/j.1432-0436.2007.00263.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2760409PMC
September 2008

The prostate specific antigen era in the United States is over for prostate cancer: what happened in the last 20 years?

J Urol 2004 Oct;172(4 Pt 1):1297-301

Department of Urology, School of Medicine, Stanford University, Stanford, California 94305, USA.

Purpose: We assessed how well preoperative serum prostate specific antigen (PSA) reflects the largest cancer in consecutive untreated radical prostatectomies during the last 20 years at Stanford University.

Materials And Methods: A total of 1,317 consecutive radical prostatectomies were divided into 4, 5-year periods between August 1983 and July 2003, and examined sequentially in 3 mm step sections by 1 pathologist. The largest cancer and 5 other histological variables in each prostate were measured. Preoperative clinical stages were tabulated for each 5-year period. Means, Pearson correlation coefficients, % change and multiple regression were used to compare selected variables.

Results: Most parameters decreased linearly during the 20 years, including palpable nodules on digital rectal examination from 91% to 17%, mean age from 64 to 59 years, mean serum PSA from 25 to 8 ng/ml, and index (largest) cancer volume from 5.3 to 2.4 cc. Percent Gleason grade 4/5 of the largest cancer averaged 27% to 35% and prostate weight 44 to 53 gm. Contrasting August 1983 to December 1988 with January 1999 to July 2003, 6 histological cancer parameters had statistically significant relationships to serum PSA in the first period. In the last 5 years serum PSA was related only to prostate size.

Conclusions: Serum PSA was related to prostate cancer 20 years ago. In the last 5 years serum PSA has only been related to benign prostatic hyperplasia. There is an urgent need for serum markers that reflect the size and grade of this ubiquitous cancer.
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http://dx.doi.org/10.1097/01.ju.0000139993.51181.5dDOI Listing
October 2004

Genetic profiling of Gleason grade 4/5 prostate cancer: which is the best prostatic control tissue?

J Urol 2003 Dec;170(6 Pt 1):2263-8

Department of Urology, School of Medicine, Stanford University, California 94305, USA.

Purpose: We examined the variation in gene expression profiles of prostate cancer caused by zone specific genes.

Materials And Methods: Ten normal central zone, 10 transition zone (benign prostatic hyperplasia) and 6 normal peripheral zone tissues from radical retropubic prostatectomies were compared to each other and to 12 peripheral zone Gleason grade 4/5 cancers. Test chips and HuGeneFL6800 (Affymetrix, Inc., Santa Clara, California) chips were used to assay the transcribed genes. Data were obtained with the Microarray Suite Version 4.0.1 (Affymetrix, Inc.) and analyzed statistically.

Results: Substantially different gene expression profiles were found depending upon which of the 3 zonal tissues were used as a control. All 3 profiles were compared for efficiency (ability to locate genes) and for robustness (the magnitude of difference between the control and the Gleason grade 4/5 tissue). Microscopically normal appearing peripheral zone tissue at the gene level shows many characteristics of Gleason grade 4/5 cancer.

Conclusions: Gene expression profiles of prostate cancer are affected by the zonal location of the control tissue and the cancer.
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http://dx.doi.org/10.1097/01.ju.0000096414.25583.0dDOI Listing
December 2003

Prognostic factors for multifocal prostate cancer in radical prostatectomy specimens: lack of significance of secondary cancers.

J Urol 2003 Aug;170(2 Pt 1):459-63

Department of Urology, Kurume University School of Medicine, Japan.

Purpose: We evaluated secondary cancers in the prostate in relation to predictions of pathological stage and prognosis.

Materials And Methods: A total of 222 men with T1c (impalpable) prostate cancer and 6 or more systematic needle biopsies were matched with radical prostatectomy and classified into 3 groups according to tumor multifocality and secondary cancer volumes, including a single tumor in 54 (24%), an index (largest) tumor with secondary cancers less than 0.5 cc in 86 (39%) and an index tumor with secondary cancers greater than 0.5 cc in 82 (37%). Logistic analysis was used to predict adverse histological features. Cox proportional hazards analysis was used to predict prostate specific antigen (PSA) failure after radical prostatectomy.

Results: There were no differences among the 3 groups with respect to preoperative serum PSA, number of positive cores, percent Gleason grade 4/5 cancer in the needle biopsy or histological features in radical prostatectomy specimens. On logistic analysis neither serum PSA nor pre-radical biopsy predicted adverse histological features in radical prostatectomy specimens. The Cox regression model showed that primary predictors of PSA failure were percent Gleason grade 4/5 cancer in the biopsy (HR = 2.6, p = 0.015) and prostatectomy (HR = 2.4, p = 0.04) specimens, and the number of positive cores (HR = 2.5, p = 0.04). When comparing PSA failure rates among the 3 groups, the multifocal group with smaller secondary cancers showed a better prognosis than the single tumor group (p = 0.019).

Conclusions: Secondary cancers in multifocal prostate tumors did not adversely influence the results of preoperative clinical parameters, including PSA and needle biopsy findings. Percent Gleason grade 4/5 cancer in needle biopsies and prostatectomy specimens is the most powerful predictor of biochemical failure in men with stage T1c prostate cancer after radical prostatectomy.
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http://dx.doi.org/10.1097/01.ju.0000070928.49986.04DOI Listing
August 2003

Hepsin and maspin are inversely expressed in laser capture microdissectioned prostate cancer.

J Urol 2003 Apr;169(4):1316-9

Department of Urology, School of Medicine, Stanford University, Stanford, California 94305, USA.

Purpose: Recent studies have shown that hepsin, a serine protease, is over expressed in prostate cancers, implicating hepsin activity in tumor invasion. Using microarray technology we have previously identified 22 genes that were up-regulated in high grade prostate cancers compared with benign prostatic hyperplasia. Of them hepsin was the most differentially over expressed. In the current report we compare hepsin to maspin (BD Transduction Laboratories, San Diego, California), a serine protease inhibitor (serpin), to measure the balance between levels of serine proteases and serpins, which are considered to be a critical determinant of net proteolytic activity.

Materials And Methods: We combined the technique of laser capture microdissection with gene expression monitoring by micro-array analysis to investigate the gene expression profiles of prostate cells of different histological types. We also studied maspin immunohistochemically.

Results: We observed that hepsin as well as 7 of 22 previously reported up-regulated genes demonstrated a pattern of increasing expression with increasing malignant phenotype. In contrast, the expression of maspin (a serpin) decreased with increasing malignancy of prostate cancers. Using immunohistochemistry we observed that maspin protein is expressed strongly in benign prostatic tissues and slightly in grade 3 prostate cancers, and is absent in grade 4/5 cancers.

Conclusions: We conclude that the increased ratio of hepsin-to-maspin may have an important role in prostate cancer progression and invasion.
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http://dx.doi.org/10.1097/01.ju.0000050648.40164.0dDOI Listing
April 2003