Prostatic Neoplasms: Thrasher JB

Thompson I, Thrasher JB, Aus G, Burnett AL, Canby-Hagino ED, Cookson MS, D'Amico AV, Dmochowski RR, Eton DT, Forman JD, Goldenberg SL, Hernandez J, Higano CS, Kraus SR, Moul JW, Tangen CM, Anonymous00324. · American Urological Association Education and Research, Inc. · J Urol. · Pubmed #17509297 No free full text.

This publication has no abstract.

Karan D, Holzbeierlein J, Thrasher JB. · Veterans Affairs Medical Center, 4801 Linwood Boulevard, Kansas City, MO 64128, USA. · Cancer Res. · Pubmed #19117979 No free full text.

Abstract: There is emerging evidence that inflammation may lead to prostate cancer development. Although inflammation is an essential response to injury or infection, chronic inflammation is harmful and causes tissue damage. Increasing evidence suggests that inflammation leads to the development of epithelial cancers; however, studies on inflammation-targeted genes that might contribute to the development of cancer are at the beginning stage. Here, we describe macrophage inhibitory cytokine-1, which provides a potential link between inflammation and prostate cancer. Understanding the regulation of macrophage inhibitory cytokine-1 in response to inflammation may have potential for novel therapeutic strategies.

Babaian RJ, Donnelly B, Bahn D, Baust JG, Dineen M, Ellis D, Katz A, Pisters L, Rukstalis D, Shinohara K, Thrasher JB. · American Urological Association Education and Research, Inc., USA. · J Urol. · Pubmed #18817934 No free full text.

This publication has no abstract.

Karan D, Thrasher JB, Lubaroff D. · Department of Urology, University of Kansas Medical Center, Kansas City, KS 66160, USA. · Prostate Cancer Prostatic Dis. · Pubmed #18283297 No free full text.

Abstract: Prostate cancer remains the most prevalent noncutaneous cancer, leading to almost 30,000 deaths every year in men in the United States. A large body of knowledge emphasizes a strong influence of epidemiological factors such as lifestyle, environment and diet, on the development of prostate cancer. Although risk reduction of prostate cancer has been somewhat successful, effective prevention is still lacking. Immunotherapeutic approaches, although moderately complicated, remain promising in an effort to control the progression and development of the disease. Taken together, the parameters of epidemiological studies and immunotherapeutic regimens might eventually be the most effective and preventive approach for prostate cancer. This review highlights some of the events associated with the development and prevention of prostate cancer.

Burnett AL, Aus G, Canby-Hagino ED, Cookson MS, D'Amico AV, Dmochowski RR, Eton DT, Forman JD, Goldenberg SL, Hernandez J, Higano CS, Kraus S, Liebert M, Moul JW, Tangen C, Thrasher JB, Thompson I, Anonymous00008. · The Johns Hopkins Hospital, 600 North Wolfe St., Marburg 407, Baltimore, Maryland 21287-2411, USA. · J Urol. · Pubmed #17570435 No free full text.

Abstract: PURPOSE: In conjunction with the assignment to update the Guidelines for Management of Clinically Localized Prostate Cancer, the American Urological Association Prostate Cancer Guideline Update Panel performed a side analysis of the reporting of erectile function outcomes in this clinical context as published in the medical literature. MATERIALS AND METHODS: Four National Library of Medicine PubMed(R) Services literature searches targeting articles published from 1991 through early 2004 were done to derive outcome reporting (efficacy or side effects) for the treatment of clinical stage T1 or T2 N0M0 prostate cancer. A database was constructed containing descriptions relating to erectile function as well as numerical frequency rates of complete erectile dysfunction, and partial and intact erectile function for various treatments. A literature review was also done, consisting of a PubMed Services search of current measures and protocols used for assessing erectile function outcomes and a survey of consensus opinion sources on the management of male sexual dysfunctions. RESULTS: Based on inclusion criteria 436 articles were selected. Of these articles database extraction from 100 pertaining to radical prostatectomy garnered various characterizations of erectile function, including qualitative descriptions, generic terminology and rating systems. Database extraction from 31 articles, in which results for at least 50 patients were reported, yielded ranges of rates for complete erectile dysfunction, partial erectile function and intact erectile function that were 26% to 100%, 16% to 48% and 9% to 86% for radical prostatectomy, 8% to 85%, 21% to 47% and 36% to 63% for external beam radiation, and 14% to 61%, 21% and 18% for interstitial radiation, respectively. The literature review showed an evolution in standards for studying and reporting erectile function outcomes. CONCLUSIONS: Clinical studies reporting erectile function outcomes after localized prostate cancer treatment often demonstrate poorly interpretable and inconsistent manners of assessment as well as widely disparate rates of erectile dysfunction and erectile function. Future studies must apply scientifically rigorous methodology and standard outcomes measures to advance this field of study.

Goetzl MA, Van Veldhuizen PJ, Thrasher JB. · Department of Urologic Surgery, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA. · Prostate Cancer Prostatic Dis. · Pubmed #17310260 No free full text.

Abstract: Worldwide disparities exist between geographic regions with regard to prostate cancer incidence and mortality. Countries in East Asia have lower rates of prostate cancer compared with Western countries such as Canada and the US. Some suggest that dietary differences between the two geographic regions, particularly the higher amount of phytoestrogens consumed in East Asia, is responsible for the difference in prostate cancer incidence. The mechanism of action of the soy isoflavones is incompletely understood, but in regards to prostate carcinogenesis likely involves estrogenic effects, cell cycle inhibition, anti-angiogenesis and induction of apoptosis. Recent clinical studies have provided mixed results with regard to a clear association between prostate cancer and soy consumption. Further studies are needed to understand more clearly the relationship between soy consumption and prostatic diseases.

Cookson MS, Aus G, Burnett AL, Canby-Hagino ED, D'Amico AV, Dmochowski RR, Eton DT, Forman JD, Goldenberg SL, Hernandez J, Higano CS, Kraus SR, Moul JW, Tangen C, Thrasher JB, Thompson I. · Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA. · J Urol. · Pubmed #17222629 No free full text.

Abstract: PURPOSE: The American Urological Association Prostate Guideline Update Panel was charged with updating the Guidelines for Clinically Localized Prostate Cancer. In assessing outcomes with treatment, it became apparent that a highly variable number of definitions exist with respect to biochemical recurrence. Herein, we review the variability in published definitions of biochemical recurrence and make recommendations directed toward improving this terminology by recommending a standard definition in patients treated with radical prostatectomy. MATERIALS AND METHODS: Four PubMed literature searches were performed between May 2001 and April, 2004 and covered articles published from 1991 through early 2004. The search terms included the MeSH major headings of prostate cancer and prostatic neoplasm. All potentially relevant articles were retrieved and a more detailed screen for relevance was performed. An article was considered relevant if it reported treatment outcomes of patients with clinical T1 or T2N0M0 prostate cancer. Data extractors recorded the definition of biochemical recurrence and definitions were then collapsed into categories representing the same criteria. The results of biochemical failure were subcategorized by initial treatment. RESULTS: Of 13,800 citations, a total of 436 articles were selected. Among these, a total of 145 articles contained 53 different definitions of biochemical recurrence for those treated with radical prostatectomy. Of these, the most common definition (35) was a prostate specific antigen of >0.2 ng/mL or a slight variation thereof. In addition, a total of 208 articles reported 99 different definitions of biochemical failure among those treated with radiation therapy. Of these, the American Society for Therapeutic Radiology and Oncology definition (70) and/or a variation thereof was the most commonly reported. In total, 166 different definitions of biochemical failure were identified. Following radical prostatectomy, the Panel recommends defining biochemical recurrence as an initial serum prostate specific antigen of > or =0.2 ng/mL, with a second confirmatory level of prostate specific antigen of >0.2 ng/mL. The Panel recommends the use of the American Society for Therapeutic Radiology and Oncology criteria for patients treated with radiation therapy and acknowledges that these criteria will soon be updated although not yet published. CONCLUSIONS: A high degree of variability in the definition of biochemical recurrence exists following treatment for localized prostate cancer. Strict definitions for biochemical recurrence are necessary to identify men at risk for disease progression and to allow meaningful comparisons among patients treated similarly. The Panel acknowledges the American Society for Therapeutic Radiology and Oncology criteria and future modifications thereof for those receiving radiation therapy and recommends the newly developed American Urological Association criteria for those treated with radical prostatectomy. The purpose for the establishment of this standard is for data reporting purposes and for comparison of similarly treated patients. It is not intended to represent a threshold value for which to initiate treatment. The Panel acknowledges that the clinical decision to initiate treatment will be dependent on multiple factors including patient and physician interaction rather than a specific prostate specific antigen threshold value.

Holzbeierlein JM, McIntosh J, Thrasher JB. · Department of Urology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA. · Curr Opin Urol. · Pubmed #15586024 No free full text.

Abstract: PURPOSE OF REVIEW: As alternative medicine gains popularity in the US, a greater understanding of the proven benefits and detriments of the supplements commonly used is needed by physicians. Chemoprevention through the use of supplements or dietary means is one example. Through epidemiological studies, it is clear that there is variation in the geographic incidence of certain cancers. One such variation is in prostate cancer, for which Asian men have a decreased death rate as compared with their Western counterparts. One hypothesis for this reduction in prostate cancer deaths is due to the difference in soy consumption. The purpose of this paper is to review the effects of soy at the molecular level as well as to review the in-vivo effects. RECENT FINDINGS: The mechanism by which soy or, more accurately, the isoflavones act is described in this review. Multiple studies attempting to clarify the effects of the isoflavones on molecular pathways will be discussed. Furthermore, recent studies demonstrating the effect of isoflavones on prostate-specific antigen, testosterone, estrogen, and hormone receptor expression in human subjects will be reviewed. SUMMARY: After reading this review, we expect that the reader will understand the background of the isoflavones, the effect they exert at the molecular level, and their proposed benefits and limitations in human patients. However, what will be evident at the conclusion of this manuscript is the need for future studies of the effects of soy in prostate cancer patients.

Holzbeierlein JM, McLaughlin MD, Thrasher JB. · Department of Urology, University of Kansas Medical Center, Kansas City, 66160, USA. · Curr Opin Urol. · Pubmed #15069309 No free full text.

Abstract: PURPOSE OF REVIEW: Androgen deprivation as a form of treatment for prostate cancer has been used for decades. Within the last decade, however, there has been a significant increase in its use. Therefore, it is incumbent upon the physician to be familiar with the side effects associated with this treatment. RECENT FINDINGS: Some of the side effects such as osteoporosis, changes in lipid profiles, and anemia may have significant morbidity associated with them, while other side effects such as impotence, decreased libido, fatigue, and hot flashes primarily affect the patient's quality of life. Prevention strategies and treatments exist for many of these side effects. SUMMARY: This review will update physicians treating patients with androgen deprivation therapy on the side effects associated with this treatment. Once physicians are aware of the potential side effects, they can educate patients on what to expect when starting androgen deprivation therapy. More importantly, physicians can now prevent some of these complications prior to their occurrence, and when these complications occur they have knowledge of the latest treatments.

Holzbeierlein JM, Castle E, Thrasher JB. · University of Kansas Medical Center, Kansas City, Kansas 66160, USA. · Oncology (Williston Park). · Pubmed #15065701 No free full text.

Abstract: Androgen deprivation, as a form of treatment for prostate cancer, has been used for decades. Within the last decade, however, its use has increased significantly. Therefore, it is incumbent upon the physician to be familiar with the side effects associated with this treatment. Some of these side effects (eg, osteoporosis, changes in lipid profiles, and anemia) may be associated with significant morbidity, whereas others (eg, impotence, decreased libido, fatigue, and hot flashes) primarily affect the patient's quality of life. Prevention strategies and treatments exist for many of these side effects. In addition, alternative forms of antiandrogen therapy such as intermittent hormone ablation and antiandrogen monotherapy may be effective, with the added benefit of minimizing side effects. This review focuses on the wide range of side effects associated with androgen ablation as well as preventive and treatment strategies.

Holzbeierlein JM, Castle EP, Thrasher JB. · Department of Urology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Mail Stop 3016, Kansas City, KS 66160, USA. · Clin Prostate Cancer. · Pubmed #15040857 No free full text.

Abstract: With the increasing indications for the use of androgen-deprivation therapy in the treatment of men with prostate cancer, side effects of the therapy deserve greater attention. Side effects such as hot flashes, decreased libido, decreased sexual function, and fatigue primarily affect the patients quality of life. Other side effects such as osteoporosis and changes in lipid profiles may also affect the patients overall health. Treatments such as estrogen, megestrol acetate, antidepressants, and bisphosphonates are useful in the management of many of the deleterious side effects of androgen deprivation. In addition, alternative management strategies such as intermittent androgen ablation and antiandrogen monotherapy may be useful in minimizing side effects caused by androgen ablation. Patients and physicians should be well aware of the potential side effects of androgen-deprivation therapy as well as the preventive and treatment strategies for these side effects in order to improve patients quality of life and health.

Castle EP, Thrasher JB. · Department of Surgery, Division of Urology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA. · Urol Clin North Am. · Pubmed #12109358 No free full text.

Abstract: Epidemiological data of phytoestrogens and prostate cancer strongly supports the cancer protective effects of isoflavones found in soy products. Inhibition of cell proliferation via hormone-dependent and hormone-independent mechanisms by soy phytochemicals has been studied extensively in cell culture and animal studies. Herein, we review the current literature on the epidemiology and effects of two soy phytoestrogens, genistein and daidzein, and would stress the need for controlled human trials to assess the true preventive and therapeutic effects of these compounds.

Thrasher JB, Deeths J, Bennett C, Iyer P, Dineen MK, Zhai S, Figg WD, McLeod DG. · Section of Urology, University of Kansas Medical Center, Kansas City, Kansas 66160-7390, USA. · Mol Urol. · Pubmed #11062382 No free full text.

Abstract: PURPOSE: We performed a randomized trial to compare the efficacy and toxicity of a new dose of flutamide (500 mg QD) with the currently recommended dose (250 mg q8h) in the treatment of advanced prostate cancer. The primary endpoints were percent of patients having normalization of prostate specific antigen (PSA), time to normalization, and percent change from baseline. Secondary endpoints were quality of life and toxicity. PATIENTS: Altogether, 440 men aged 46 to 94 years (mean 71 years) with confirmed stage M(1) disease, documented PSA rise >0.2 ng/mL, ECOG status 0 to 2, no second neoplasm, no liver function tests > or = 1.5-fold normal values, and no previous treatment for metastatic disease were entered in the trial. RESULTS: The PSA normalized by week 12 in 71% of the patients receiving 500-mg dose and 75% of those receiving the standard dose. The percent change in PSA was 89% and 96%, respectively. The treatment groups were not significantly different with respect to the incidence of adverse events: 71% v 68% in the 500-mg and 250-mg arms, respectively (P = 0.337). CONCLUSIONS: When combined with castration, 500 mg of flutamide appears to be equally effective in lowering serum PSA and is not significantly more toxic than conventional dosing. The use of 500 mg QD instead of the standard 250 mg q8h would result in a cost savings of 30%.

Goetzl MA, Krebill R, Griebling TL, Thrasher JB. · Department of Urology, University of Kansas Medical Center, Kansas City, Kansas, USA. · Can J Urol. · Pubmed #19364427 No free full text.

Abstract: INTRODUCTION/OBJECTIVE: Margin positivity has been a well described adverse prognostic factor in patients undergoing radical prostatectomy. Previous studies with regards to predictors of margin positivity after prostatectomy have primarily focused on the retropubic or robotic approach. We sought to examine the predictors of margin positivity in a contemporary series of men undergoing radical perineal prostatectomy (RPP). MATERIALS AND METHODS: We reviewed the records of 103 patients who underwent RPP at our institution from July 1998 until May 2008. A positive surgical margin (PSM) was defined as the presence of cancer cells at the inked margin of the surgical specimen. Records were reviewed for the following preoperative parameters: age at operation, body mass index (BMI), preoperative PSA, clinical stage and biopsy Gleason sum score. Pathological data included prostate weight (PW) and tumor volume. RESULTS: Mean age was 60.9 (range 45-76). Mean BMI was 31.4 kg/m2 (20.9-51.6). The preoperative prevalence of palpable disease was 50.5%. A PSM was found in 23.3%. Age, BMI, clinical stage, biopsy Gleason sum score and preoperative PSA were not found to be independent predictors of a PSM after RPP. Only prostate weight was found to be a significant preoperative predictor of a PSM after RPP with men with smaller prostates at higher risk. CONCLUSIONS: Prostate weight was found to be significantly and inversely related to the PSM rate in this cohort of RPP patients. Patients with smaller volume prostates should be counseled preoperatively that they are at higher risk for a PSM when undergoing a RPP.

Bass R, Perry B, Langenstroer P, Thrasher JB, Dennis KL, Tawfik O, Holzbeierlein J. · Department of Urology, University of Kansas Hospital, Kansas City, Kansas 66160, USA. · J Urol. · Pubmed #19091346 No free full text.

Abstract: PURPOSE: We explored the molecular correlates of the effect of finasteride on prostate tissue in patients undergoing radical prostatectomy. MATERIALS AND METHODS: Patients undergoing radical prostatectomy for localized prostate cancer were eligible for study. After providing informed consent patients were randomized to receive 5 mg finasteride or placebo daily for at least 30 days before surgery. At surgery prostate tissue was harvested from the surgical specimen and sent for analysis. Tissue samples were analyzed for the pro-apoptotic factors caspase-3, caspase-7 and IGFBP-3. Samples were also analyzed for the tumor suppressor/proto-oncoproteins bcl-2, p53 and p21. Finally, tissues were analyzed for androgen receptor density and insulin growth factor-1. RESULTS: A total of 22 study and 20 placebo samples were collected and analyzed. Negligible staining for bcl-2 or caspase-3 was noted in each group. Statistical differences were not observed for bcl-2, p53, p21 or insulin growth factor-1 between the groups. There was a statistically significant difference in caspase-7 and IGFBP-3. A mean of 77% and 99.9% of cells stained for caspase-7 in the treatment and placebo groups, respectively (p = 0.007). In 3 patients caspase-7 staining disappeared completely and it was decreased by 70% and 50% in 1 patient each. Mean intensity staining for IGFBP-3 was 1.03 in the treatment group and 1.54 in the placebo group (p = 0.005). The staining intensity of nuclear androgen receptors on benign and cancerous cells was not significantly different between the treatment and placebo groups. However, there was a significant difference in androgen receptor staining between benign and cancer cells in the 2 populations. Mean nuclear androgen receptor staining intensity in all cancer and all benign tissue samples was 119.3 and 151.8, respectively (0.001). CONCLUSIONS: Finasteride administered 30 days before surgery appears to decrease the apoptotic factors caspase-7 and IGFBP-3 in cancer cells, while having little to no effect on caspase-3, insulin growth factor-1, bcl-2, p53 and p21. This short-term study may have interesting implications for interpreting Prostate Cancer Prevention Trial data on the molecular level. No differences were noted between the treatment and placebo groups in the expression of nuclear androgen receptor. However, decreased expression of androgen receptors was present in cancer cells compared to that in benign prostate cells in the 2 groups.

Zhu Q, Youn H, Tang J, Tawfik O, Dennis K, Terranova PF, Du J, Raynal P, Thrasher JB, Li B. · Department of Medical Oncology, The First Affiliated Hospital, Xi'An Jiaotong University, College of Medicine, Xi'An, China. · Oncogene. · Pubmed #18372911 links to  free full text

Abstract: Phosphoinositide 3-OH kinases (PI3Ks) are a group of major intracellular signaling molecules. In our previous study, we found that inhibition of PI3K activity suppressed the androgen receptor (AR)-mediated gene expression in prostate cancer cells. The AR has been considered as a critical determinant for the development and progression of human prostate cancers. In this study, we sought to identify the PI3K isoforms involved in AR transactivation. Using a gene-specific small interference RNA (siRNA) approach, we determined that the regulatory isoform p85alpha and the catalytic isoform p110beta, but not p110alpha, were required for androgen-stimulated AR transactivation and cell proliferation in prostate cancer cells. Consistently, overexpression of wild-type p110beta but not p110alpha gene led to androgen-independent AR transactivation. Silencing p110beta gene in prostate cancer cells abolished tumor growth in nude mice. Of the dual (lipid and protein) kinase activities, p110beta's lipid kinase activity was required for AR transactivation. Further analysis by a chromatin immunoprecipitation assay showed that p110beta is indispensable for androgen-induced AR-DNA interaction. Finally, gene expression analysis of clinical specimens showed that both p85alpha and p110beta were highly expressed in malignant prostate tissues compared to the nonmalignant compartments, and their expression levels correlated significantly with disease progression. Taken together, our data demonstrated that p85alpha and p110beta are essential for androgen-stimulated AR transactivation, and their aberrant expression or activation might play an important role in prostate cancer progression.

Sun A, Tang J, Hong Y, Song J, Terranova PF, Thrasher JB, Svojanovsky S, Wang HG, Li B. · Department of Pathology, Shaoxing People's Hospital & the First Affiliated Hospital of Shaoxing University, Shaoxing, Zhejiang, China. · Prostate. · Pubmed #18196538 No free full text.

Abstract: BACKGROUND: Recently we reported that silencing the androgen receptor (AR) gene reduced Bcl-xL expression that was associated with a profound apoptotic cell death in prostate cancer cells. In this study we further investigated AR-regulated Bcl-xL expression. METHODS: Prostate cancer cell line LNCaP and its sublines, LNCaP/PURO and LNCaP/Bclxl, were used for cell proliferation assay and xenograft experiments in nude mice. Luciferase gene reporters driven by mouse or human bcl-x gene promoter were used to determine androgen regulation of Bcl-xL expression. RT-PCR and Western blot assays were conducted to assess Bcl-xL gene expression. Chromatin immunoprecipitation assay was performed to determine AR interaction with Bcl-xL promoter. Bcl-xL-induced alteration of gene expression was examined using cDNA microarray assay. RESULTS: In cultured prostate cancer LNCaP cells, androgen treatment significantly increased Bcl-xL expression at mRNA and protein levels via an AR-dependent mechanism. Promoter analyses demonstrated that the AR mediated androgen-stimulated bcl-x promoter activation and that the AR interacted with bcl-x promoter. Enforced expression of Bcl-xL gene dramatically increased cell proliferation in vitro and promoted xenograft tumor growth in vivo. Genome-wide gene profiling analysis revealed that Bcl-xL expression was significantly higher in metastatic and castration-resistant diseases compared to normal prostate tissues or primary cancers. Bcl-xL overexpression significantly increased the expression of cyclin D2, which might be responsible for Bcl-xL-induced cell proliferation and tumor growth. CONCLUSIONS: Taken together, our data strongly suggest that androgen stimulates Bcl-xL expression via the AR and that increased Bcl-xL expression plays a versatile role in castration-resistant progression of prostate cancer.

Sun A, Shanmugam I, Song J, Terranova PF, Thrasher JB, Li B. · Department of Pathology, Shaoxing People's Hospital and the First Affiliated Hospital of Shaoxing University, Shaoxing, Zhejiang, China. · Prostate. · Pubmed #17440966 No free full text.

Abstract: BACKGROUND: Lithium is an existing drug for bipolar disorder and its uptake was recently linked to reduced tumor incidence compared to the general population. The major target of lithium action is glycogen synthase kinase 3 (GSK-3). Since GSK-3 expression and activation are associated with prostate cancer progression, the anti-cancer potential of lithium on prostate cancer was investigated in this study. METHODS: Multiple prostate cancer cell lines were treated with lithium chloride (LiCl). Cell proliferation and cell cycle distribution were analysed. DNA replication was determined using BrdU labeling assay. Genome-wide screening of gene expression was performed using cDNA microarray assay. GSK-3beta gene-specific silencing was conducted using small interferencing RNA (siRNA) transfection. E2 factor (E2F) transactivation was evaluated using reporter gene assay and E2F-DNA interaction was determined with chromatin-immunoprecipitation assay (ChIP). RESULTS: LiCl significantly inhibited cell proliferation, which was associated with reduced DNA replication and S-phase cell cycle arrest. LiCl significantly decreased the expression of multiple DNA replication-related genes, including cell division cycle 6 (cdc6), cyclin A, cyclin E, and cdc25C, which are regulated by E2F factor during cell cycle. A novel GSK-3-specific inhibitor TDZD-8 and GSK-3beta siRNA also suppressed the expression of these E2F target genes, indicating that LiCl-induced anti-cancer effect was associated with GSK-3beta inhibition. Furthermore, LiCl suppressed E2F transactivation by interrupting the interaction of E2F1 factor with its target gene promoter. CONCLUSIONS: These data indicated that LiCl suppresses cancer cell proliferation by disrupting E2F-DNA interaction and subsequent E2F-mediated gene expression in prostate cancer.

van Veldhuizen PJ, Thrasher JB, Ray G, Cherian R, Ward J, Holzbeierlein J, Gutow S, Banerjee SK. · Cancer Research Unit, Veteran Affairs Medical Center and University of Kansas Medical Center, Kansas City, MO 64128, USA. · Oncol Rep. · Pubmed #17089041 No free full text.

Abstract: We performed a pilot study to determine the dose effect of soy supplement on serum hormonal levels, estrogen receptor alpha (ERalpha) and androgen receptor (AR) expression in patients scheduled to undergo prostatectomy. Cohorts of 3-4 eligible patients received escalating doses of a commercial soy supplement, Flav-ein, from the time of study enrollment until prostatectomy. Serum levels of prostate specific antigen (PSA), testosterone, and estrogen were measured at study enrollment and prior to prostatectomy. AR and ERalpha expression was evaluated in the pretreatment biopsy specimen and post-treatment prostatectomy specimen using immunohistochemical analysis. A total of 13 patients were enrolled in this pilot study and 11 patients were assessable for response. With soy supplementation, serum testosterone levels decreased in 9 of 11 patients and estrogen levels decreased in 8 of 10 patients in a dose-dependent manner. There was a variable effect on ERalpha expression with downregulation of receptor expression seen at the highest dose level. There was no effect on AR expression. In conclusion, supplementation with this commercial soy product produced a consistent decrease in serum sex hormone levels. Additional studies are needed to evaluate a potential dose effect on ERalpha expression.

Sun A, Tawfik O, Gayed B, Thrasher JB, Hoestje S, Li C, Li B. · Department of Pathology, Shaoxing People's Hospital, First Affiliated Hospital of Shaoxing University, Shaoxing, Zhejiang, China. · Prostate. · Pubmed #17075831 No free full text.

Abstract: BACKGROUND: Brahma gene (BRM) and Brahma-related gene 1 (BRG1) are major components with ATPase enzymatic activities in the nucleosome remodeling SWI/SNF complex, and their expression pattern in human prostate cancers is unknown. METHOD: We analyzed a published cDNA microarray data set of prostate cancers for the expression of SWI/SNF genes, and then we evaluated the expression levels of BRG1 and BRM proteins with a semi-quantitative immunohistochemistry (IHC) approach in a pairwise manner of malignant versus benign tissues from individual prostate cancers. The correlation of BRG1/BRM expression with clinical parameters was analyzed. RESULTS: Microarray data showed an aberrant expression of BRG1 and BRM but not SNF5/INI1 genes in different stages of the disease course. In immunochemistry studies, BRG1 expression was significantly higher in malignant tissues compared to their benign compartments, and this difference was more profound in high-grade cancers. Although BRM expression showed a heterogeneous pattern, the average level of BRM expression was lower in malignant tissues than that in benign tissues. More interestingly, BRG1 and BRM expression showed a reciprocal pattern in both benign and malignant tissues of individual cases. In malignant tissues, higher BRG1 but not BRM expression levels were associated with larger volume of tumor mass. Increased expression of BRG1 but not BRM protein was observed in invasive cancer cells. Consistently, overexpression of exogenous wild-type BRG1 and BRM but not mutant BRG1 enhanced cancer cell invasion in an in vitro cell invasion assay. CONCLUSIONS: We provide the first evidence that aberrant expression of BRG1 and BRM genes is associated with disease development and progression in prostate cancers and increased BRG1 expression may promote tumor growth and invasion.

Li B, Sun A, Youn H, Hong Y, Terranova PF, Thrasher JB, Xu P, Spencer D. · Department of Urology, The University of Kansas Medical Center Kansas City, KA 66160, USA. · Carcinogenesis. · Pubmed #17032658 links to  free full text

Abstract: Aggressive androgen-independent (also termed as hormone-refractory) prostate cancer is a major clinical obstacle because there is no means to cure. Previous studies have shown that Akt activation is associated with prostate cancer progression from androgen-dependent to androgen-independent stage. However, its causative role in this process has not been established. One of the major limitations is the lack of a well-controlled inducible system to study Akt involvement. Recently, we developed a novel inducible Akt (iAKT) system based on a chemically induced dimerization (CID) approach. This system allows for conditional activation of Akt in a physiological setting. Utilizing this iAKT system, we found that Akt activation prevented cell death after serum withdrawal and promoted cell proliferation in the absence of androgen in vitro in human prostate cancer LNCaP cells, which should stop growing after androgen withdrawal or even die after serum starvation. The iAKT-induced death protection and growth promotion were further demonstrated in vivo using a transgenic mouse model that expresses the iAKT system conditionally in the prostate epithelium. Most importantly, in a mouse xenograft model derived from LNCaP cells, iAKT activation promoted tumor growth in castrated animals by enhancing cell proliferation and inhibiting apoptosis. Taken together, our data suggest that Akt activation is playing a causative role in androgen-independent progression of prostate cancer. This study provides a significant relevance of Akt-targeted therapy for hormone-refractory prostate cancers.

Li BY, Liao XB, Fujito A, Thrasher JB, Shen FY, Xu PY. · Department of Urology, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA. · Asian J Androl. · Pubmed #16888681 links to  free full text

Abstract: AIM: To characterize the matrix metalloproteinases (MMP)-2 promoter and to identify androgen response elements (AREs) involved in androgen-induced MMP-2 expression. METHODS: MMP-2 mRNA levels was determined by reverse transcription-polymerase chain reaction (RT-PCR). MMP-2 promoter-driven luciferase assays were used to determine the fragments responsible for androgen-induced activity. Chromatin-immunoprecipitation assay and electrophoretic mobility shift assays (EMSA) were used to verify the identified AREs in the MMP-2 promoter. RESULTS: Androgen significantly induced MMP-2 expression at the mRNA level, which was blocked by the androgen antagonist bicalutamide. Deletion of a region encompassing base pairs -1591 to -1259 (relative to the start codon) of the MMP-2 promoter led to a significant loss of androgen-induced reporter activity. Additional deletion of the 5'-region up to -562 bp further reduced the androgen-induced MMP-2 promoter activity. Sequence analysis of these two regions revealed two putative ARE motifs. Introducing mutations in the putative ARE motifs by site-directed mutagenesis approach resulted in a dramatic loss of androgen-induced MMP-2 promoter activity, indicating that the putative ARE motifs are required for androgen-stimulated MMP-2 expression. Most importantly, the androgen receptor (AR) interacted with both motif-containing promoter regions in vivo in a chromatin immunoprecipitation assay after androgen treatment. Furthermore, the AR specifically bound to the wild-type but not mutated ARE motifs-containing probes in an in vitro EMSA assay. CONCLUSION: Two ARE motifs were identified to be responsible for androgen-induced MMP-2 expression in prostate cancer cells.

Langenstroer P, Kramer B, Cutting B, Amling C, Poultan T, Lance R, Thrasher JB. · Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. · J Urol. · Pubmed #16006929 No free full text.

Abstract: PURPOSE: Luteinizing hormone releasing hormone (LHRH) agonist therapy for advanced prostate cancer can manifest significant side effects affecting quality of life, most notably hot flashes. This study evaluated the effectiveness of parenteral medroxyprogesterone acetate (MPA) in reducing the frequency and severity of these hot flashes. MATERIALS AND METHODS: A multi-institutional retrospective review of hot flashes from LHRH therapy for prostate cancer was conducted. The hot flashes were quantified and the severity was graded (3-point analogue scale) before and after treatment with MPA. Two doses of MPA (400 or 150 mg intramuscularly) were administered. Statistical analysis (Student's t test) evaluated the quantity of hot flashes, the quality of hot flashes, and dose effectiveness. RESULTS: A total of 48 men (40 at 400 mg, 8 at 150 mg) with a mean age of 71.4 years (range 54 to 87) from 3 institutions were evaluated. There were 91% with symptomatic improvement with MPA, and half (46%) had a complete response defined as total elimination of hot flashes. The median number of the hot flashes per day decreased from 4 to 1 and the median severity score decreased from 2 to 1 (p <0.05). Significance was not achieved comparing the 2 doses. Complete responders were not noted with the 150 mg dose. Anticipated response to MPA did not correlate with the number or severity of the hot flashes. CONCLUSIONS: This study is the first multi-institutional evaluation of hot flashes demonstrating significant reduction in quantity and severity with MPA. Based on these data we now manage hot flashes associated with LHRH analogues with 400 mg of MPA.

Langenstroer P, Carroll P, Thrasher JB. · Medical College of Wisconsin, Milwaukee, Wisconsin, USA. · J Urol. · Pubmed #15947594 No free full text.

Abstract: PURPOSE: The new and older clinical staging systems for prostate cancer overlook a group of patients in whom abnormal digital rectal examinations (DREs) do not correlate with prostate biopsy findings. These cases are clinically unstageable. We evaluated the prevalence and pathological characteristics of these patients and stratified them into the 1997 American Joint Committee on Cancer clinical staging categories. MATERIALS AND METHODS: Using the CaPSURE database, a longitudinal disease registry of patients with various stages of prostate cancer, the unstageable cohort was identified. The postoperative pathological stage distribution of the unstageable cohort was used to assign the appropriate preoperative clinical stages in retrograde fashion. Pearson product moment correlation was used to establish the best clinical stage for this unstageable group. RESULTS: A total of 5,543 patients with recorded DREs were evaluated, of whom 2,610 (47%) had an isolated unilateral abnormality on DRE. A total of 235 patients (9%) had prostate needle biopsies positive only on the contralateral side, yielding an unstageable prevalence of 4.2%. Of the cohort 102 patients (44%) underwent radical prostatectomy and 96 had adequate pathological staging data available for review and correlation. Pathological staging revealed pT2a cancers in 26%, pT2b in 53%, pT3a in 19%, pT3b and pT0 in 1% of patients. This distribution indicated that the unstageable cohort correlated most precisely with clinical stage T1c (r = 0.99). CONCLUSIONS: Thus, the prevalence of unstageable prostate cancer is low but significant and it can be accurately classified into clinical stage T1c.

Liao X, Tang S, Thrasher JB, Griebling TL, Li B. · Department of Urology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, Kansas 66160, USA. · Mol Cancer Ther. · Pubmed #15827323 links to  free full text

Abstract: Prostate cancer is the second leading cause of cancer death in the United States and, thus far, there has been no effective therapy for the treatment of hormone-refractory disease. Recently, the androgen receptor (AR) has been shown to play a critical role in the development and progression of the disease. In this report, we showed that knocking down the AR protein level by a small interfering RNA (siRNA) approach resulted in a significant apoptotic cell death as evidenced by an increased annexin V binding, reduced mitochondrial potential, caspase-3/6 activation, and DFF45 and poly(ADP-ribose) polymerase cleavage. The apoptotic response was specifically observed in those siRNA-transfected cells that harbor a native AR gene. No cell death was found in the AR-null prostate cancer cell PC-3 or its subline that has been reconstituted with an exogenous AR gene, as well as two breast cancer cell lines that are AR positive. Moreover, in parallel with the siRNA-induced AR silencing, the antiapoptotic protein Bcl-xL was significantly reduced, which might account for the apoptotic cell death because ectopic enforced expression of Bcl-xL protein partially inhibited apoptosis after AR silencing. Taken together, our data showed that knocking down the AR protein level in prostate cancer cells leads to apoptosis by disrupting the Bcl-xL-mediated survival signal downstream of AR-dependent survival pathway.