Publications by authors named "Grenville Oades"

16 Publications

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Pediatric and young adult renal cell carcinoma.

Pediatr Blood Cancer 2020 11 1;67(11):e28675. Epub 2020 Sep 1.

Department of Paediatric Oncology, Royal Hospital for Children, Glasgow, Scotland, UK.

Renal cell carcinoma (RCC) is rare in children but is the most common renal tumor in adults. Pediatric RCC has different clinical characteristics, histopathology, and treatment compared with adult disease. Databases were reviewed from inception to February 2020, identifying 32 publications pertaining to 350 patients under 27 years. Surgery is the cornerstone for cure in localized RCC. Lymph node dissection remains controversial. Conventional radiotherapy has no curative role in RCC; similarly, conventional chemotherapy has not proven to be effective in large cohorts. Pediatric metastatic RCC has a poor outlook. There are no published prospective studies demonstrating which adjuvant therapy could improve outcome. Sunitinib, a tyrosine kinase inhibitor, is recommended in this group despite limited evidence. This review provides an overview for pediatric RCC, including the evolving role of precision medicine.
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November 2020

Challenges of early renal cancer detection: symptom patterns and incidental diagnosis rate in a multicentre prospective UK cohort of patients presenting with suspected renal cancer.

BMJ Open 2020 05 11;10(5):e035938. Epub 2020 May 11.

Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK.

Objectives: To describe the frequency and nature of symptoms in patients presenting with suspected renal cell carcinoma (RCC) and examine their reliability in achieving early diagnosis.

Design: Multicentre prospective observational cohort study.

Setting And Participants: Eleven UK centres recruiting patients presenting with suspected newly diagnosed RCC. Symptoms reported by patients were recorded and reviewed. Comprehensive clinico-pathological and outcome data were also collected.

Outcomes: Type and frequency of reported symptoms, incidental diagnosis rate, metastasis-free survival and cancer-specific survival.

Results: Of 706 patients recruited between 2011 and 2014, 608 patients with a confirmed RCC formed the primary study population. The majority (60%) of patients were diagnosed incidentally. 87% of patients with stage Ia and 36% with stage III or IV disease presented incidentally. Visible haematuria was reported in 23% of patients and was commonly associated with advanced disease (49% had stage III or IV disease). Symptomatic presentation was associated with poorer outcomes, likely reflecting the presence of higher stage disease. Symptom patterns among the 54 patients subsequently found to have a benign renal mass were similar to those with a confirmed RCC.

Conclusions: Raising public awareness of RCC-related symptoms as a strategy to improve early detection rates is limited by the fact that related symptoms are relatively uncommon and often associated with advanced disease. Greater attention must be paid to the feasibility of screening strategies and the identification of circulating diagnostic biomarkers.
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May 2020

UK Multicenter Prospective Evaluation of the Leibovich Score in Localized Renal Cell Carcinoma: Performance has Altered Over Time.

Urology 2020 02 6;136:162-168. Epub 2019 Nov 6.

Leeds Institute of Medical Research at St James's, St. James's University Hospital, Leeds, UK.

Objective: To examine changes in outcome by the Leibovich score using contemporary and historic cohorts of patients presenting with renal cell carcinoma (RCC) PATIENTS AND METHODS: Prospective observational multicenter cohort study, recruiting patients with suspected newly diagnosed RCC. A historical cohort of patients was examined for comparison. Metastasis-free survival (MFS) formed the primary outcome measure. Model discrimination and calibration were evaluated using Cox proportional hazard regression and the Kaplan-Meier method. Overall performance of the Leibovich model was assessed by estimating explained variation.

Results: Seven hundred and six patients were recruited between 2011 and 2014 and RCC confirmed in 608 (86%) patients. Application of the Leibovich score to patients with localized clear cell RCC in this contemporary cohort demonstrated good model discrimination (c-index = 0.77) but suboptimal calibration, with improved MFS for intermediate- and high-risk patients (5-year MFS 85% and 50%, respectively) compared to the original Leibovich cohort (74% and 31%) and a historic (1998-2006) UK cohort (76% and 37%). The proportion of variation in outcome explained by the model is low and has declined over time (28% historic vs 22% contemporary UK cohort).

Conclusion: Prognostic models are widely employed in patients with localized RCC to guide surveillance intensity and clinical trial selection. However, the majority of the variation in outcome remains unexplained by the Leibovich model and, over time, MFS rates among intermediate- and high-risk classified patients have altered. These findings are likely to have implications for all such models used in this setting.
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February 2020

Surveillance versus ablation for incidentally diagnosed small renal tumours: the SURAB feasibility RCT.

Health Technol Assess 2017 12;21(81):1-68

Royal Free London NHS Foundation Trust, London, UK.

Background: There is uncertainty around the appropriate management of small renal tumours. Treatments include partial nephrectomy, ablation and active surveillance.

Objectives: To explore the feasibility of a randomised trial of ablation versus active surveillance.

Design: Two-stage feasibility study: stage 1 - clinician survey and co-design work; and stage 2 - randomised feasibility study with qualitative and economic components.

Methods: Stage 1 - survey of radiologists and urologists, and development of patient information materials. Stage 2 - patients identified across eight UK centres with small renal tumours (< 4 cm) were randomised (1 : 1 ratio) to ablation or active surveillance in an unblinded manner. Randomisation was carried out by a central computer system. The primary objective was to determine willingness to participate and to randomise a target of 60 patients. The qualitative and economic data were collected separately.

Results: The trial was conducted across eight centres, with a site-specific period of recruitment ranging from 3 to 11 months. Of the 154 patients screened, 36 were eligible and were provided with study details. Seven agreed to be randomised and one patient was found ineligible following biopsy results. Six patients (17% of those eligible) were randomised: three patients received ablation and no serious adverse events were recorded. The 3- and 6-month data were collected for four (67%) and three (50%) out of the six patients, respectively. The qualitative substudy identified factors directly impacting on the recruitment of this trial. These included patient and clinician preferences, organisational factors (variation in clinical pathway) and standard treatment not included. The health economic questionnaire was designed and piloted; however, the sample size of recruited patients was insufficient to draw a conclusion on the feasibility of the health economics.

Conclusions: The trial did not meet the criteria for progression and the recruitment rate was lower than hypothesised, demonstrating that a full trial is presently not possible. The qualitative study identified factors that led to variation in recruitment across the sites. Implementation of organisational and operational measures can increase recruitment in any future trial. There was insufficient information to conduct a full economic analysis.

Trial Registration: Current Controlled Trials ISRCTN31161700.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 21, No. 81. See the NIHR Journals Library website for further project information.
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December 2017

Cytoreductive Nephrectomy in the Tyrosine Kinase Inhibitor Era: A Question That May Never Be Answered.

Eur Urol 2017 06 1;71(6):845-847. Epub 2016 Nov 1.

Gustave Roussy Institute, Paris, France.

Despite great interest, two randomised controlled trials (RCTs) of cytoreductive nephrectomy in the tyrosine kinase inhibitor setting in metastatic renal cell carcinoma have either closed early (SURTIME) or are recruiting very slowly (CARMENA) after 7 yr. Challenges in RCT delivery in uro-oncologic surgery are many. Multiple steps are needed to ensure strong recruitment to trials addressing important urologic cancer questions. Feasibility/pilot studies are key stepping stones towards successful delivery of surgical RCTs.
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June 2017

Safety and Efficacy of Pazopanib Therapy Prior to Planned Nephrectomy in Metastatic Clear Cell Renal Cancer.

JAMA Oncol 2016 Oct;2(10):1303-1309

Cancer Sciences Unit, University of Southampton, Southampton, England.

Importance: The role of cytoreductive nephrectomy in patients with metastatic renal cancer in the era of targeted therapy is uncertain.

Objective: To establish the safety and efficacy of upfront pazopanib therapy prior to cytoreductive nephrectomy in previously untreated patients with metastatic clear cell renal cancer.

Design, Setting, And Participants: Single-arm phase 2 study of 104 previously untreated patients with metastatic clear cell renal cancer recruited between June 2008 and October 2012 at cancer treatment centers with access to nephrectomy services. The minimum follow-up was 30 months.

Interventions: Patients received 12 to 14 weeks of preoperative pazopanib therapy prior to planned cytoreductive nephrectomy and continued pazopanib therapy after surgery. Treatment was stopped at disease progression.

Main Outcomes And Measures: The primary end point was clinical benefit (using Response Evaluation Criteria in Solid Tumors, version 1.1) prior to surgery (at 12-14 weeks). Secondary end points included surgical complications, progression-free survival (PFS), overall survival (OS), and biomarker analysis.

Results: Of 104 patients recruited, 100 patients were assessable for clinical benefit prior to planned nephrectomy; 80 of 104 (76.9%) were men; median [interquartile range] age, 64 [56-71] years). Overall, 84 of 100 (84% [95% CI, 75%-91%]) gained clinical benefit before planned nephrectomy. The median reduction in the size of the primary tumor was 14.4% (interquartile range, 1.4%-21.1%). No patients were unable to undergo surgery as a result of local progression of disease. Nephrectomy was performed in 63 (61%) of patients; 14 (22%) reported surgical complications. The 2 most common reasons for not undergoing surgery were progression of disease (n = 13) and patient choice (n = 9). There was 1 postoperative surgical death. The median PFS and OS for the whole cohort were 7.1 (95% CI, 6.0-9.2) and 22.7 (95% CI, 14.3-not estimable) months, respectively. Patients with MSKCC poor-risk disease or progressive disease prior to surgery had a poor outcome (median OS, 5.7 [95% CI, 2.6-10.8] and 3.9 [95% CI, 0.5-9.1] months, respectively). Surgical complications were observed in 14 (22%) of the nephrectomies. Biomarker analysis from sequential tissue samples revealed a decrease in CD8 expression (20.00 vs 13.75; P = .05) and significant reduction in expression of von Hippel-Lindau tumor suppressor (100 vs 40; P < .001) and C-MET (300 vs 100; P < .001) and increased programmed cell death ligand 1 expression (0 vs 1.5; P < .001) in the immune component. No on-treatment biomarker correlated with response.

Conclusions And Relevance: Nephrectomy after upfront pazopanib therapy could be performed safely and was associated with good outcomes in patients with intermediate-risk metastatic clear cell renal cancer.
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October 2016

Thermal ablative therapies for treatment of localised renal cell carcinoma: a systematic review of the literature.

Scott Med J 2016 Nov 31;61(4):185-191. Epub 2016 May 31.

Urology Consultant. Queen Elizabeth University Hospital, Glasgow, UK.

Background And Aims: Small renal masses are commonly diagnosed incidentally. The majority are malignant and require intervention. The gold standard treatment is partial nephrectomy unless the patient has significant co-morbidities when surveillance or ablative therapies are utilised. The latter are relatively novel and their long-term efficacy and safety remain generally poorly understood. We performed a literature review to establish the current evidence on the oncological outcome of thermal ablative techniques in small renal masses treatment.

Methods And Results: A systematic literature search was performed using PubMed, supplemented with additional references. Articles were reviewed for data on indications, tumour characteristics, ablative techniques, oncological outcome, impact on renal function and complications. The vast majority of articles identified were observational studies. There has not been any direct comparison against partial nephrectomy. Radiofrequency ablation and cryoablation are the techniques that are more commonly used. They have favourable oncological results on intermediate follow-up and indications that successful outcome is sustained long term. The morbidity and impact on renal function appear to be minimal.

Conclusion: Thermal ablative therapies are valid alternatives to partial nephrectomy for the treatment of small renal masses in patients unfit for surgery. Prospective long-term data will be needed before the indications for their use expand further.
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November 2016

Nuclear expression of Lyn, a Src family kinase member, is associated with poor prognosis in renal cancer patients.

BMC Cancer 2016 Mar 16;16:229. Epub 2016 Mar 16.

Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, G61 1QH, Glasgow, Scotland, UK.

Background: 8000 cases of renal cancer are diagnosed each year in the UK, with a five-year survival rate of 50%. Treatment options are limited; a potential therapeutic target is the Src family kinases (SFKs). SFKs have roles in multiple oncogenic processes and promote metastases in solid tumours. The aim of this study was to investigate SFKs as potential therapeutic targets for clear cell renal cell carcinoma (ccRCC).

Methods: SFKs expression was assessed in a tissue microarray consisting of 192 ccRCC patients with full clinical follow-up. SFK inhibitors, dasatinib and saracatinib, were assessed in early ccRCC cell lines, 786-O and 769-P and a metastatic ccRCC cell line, ACHN (± Src) for effects on protein expression, apoptosis, proliferation and wound healing.

Results: High nuclear expression of Lyn and the downstream marker of activation, paxillin, were associated with decreased patient survival. Conversely, high cytoplasmic expression of other SFK members and downstream marker of activation, focal adhesion kinase (FAK) were associated with increased patient survival. Treatment of non-metastatic 786-O and 769-P cells with dasatinib, dose dependently reduced SFK activation, shown via SFK (Y(419)) and FAK (Y(861)) phosphorylation, with no effect in metastatic ACHN cells. Dasatinib also increased apoptosis, while decreasing proliferation and migration in 786-O and 769-P cell lines, both in the presence and absence of Src protein.

Conclusions: Our data suggests that nuclear Lyn is a potential therapeutic target for ccRCC and dasatinib affects cellular functions associated with cancer progression via a Src kinase independent mechanism.
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March 2016

Frozen section during partial nephrectomy: an unreliable test that changes nothing?

BJU Int 2015 Dec;116(6):836-7

Department of Urology, NHS Greater Glasgow and Clyde, Glasgow, UK.

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December 2015

Translational research will fail without surgical leadership: SCOTRRCC a successful surgeon-led Nationwide translational research infrastructure in renal cancer.

Surgeon 2015 Aug 30;13(4):181-6. Epub 2015 Apr 30.

Edinburgh Urological Cancer Group, University of Edinburgh, Edinburgh, UK; NHS Lothian, UK; School of Medicine, St. Andrews University, St. Andrews, UK.

Background: High quality human biosamples with associated high quality clinical data are essential for successful translational research. Despite this, the traditional approach is for the surgeon to act as a technician in the tissue collection act. Biomarker research presents multiple challenges and the field is littered with failures. Tissue quality, poor clinical information, small sample numbers and lack of validation cohorts are just a few reasons for failure. It is clear that the surgeon involved in tissue acquisition must be fully engaged in the process of biosampling for a specific condition, as this will negate many of the issues for translational research failure due to an inadequate bioresource.

Approach: In this Matter for Debate paper, the Scottish Collaboration On Translational Research into Renal Cell Cancer (SCOTRRCC) is discussed as an example of a urological surgery lead bioresource which has resulted in a National collection of renal cancer tissue and blood (from over 900 patients to date), negating all of the traditional issues with biobanks because of close enagagement and acknowledgement of urologists and uropathologists from seven centres around Scotland. SCOTRRCC has leveraged renal cancer research in Scotland resulting in several high impact publications and providing a springboard for future research in this disease in Scotland and beyond.

Conclusions: The SCOTRRCC model presented here can be transferred to other surgical disciplines for success in translational research.
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August 2015

Reclassification of the Fuhrman grading system in renal cell carcinoma-does it make a difference?

Springerplus 2013 10;2:378. Epub 2013 Aug 10.

Unit of Experimental Therapeutics, Institute of Cancer, College of MVLS, University of Glasgow, Western Infirmary, Glasgow, G11 6NT Scotland, UK.

Purpose: The aim of this study was to determine whether reclassifying the Fuhrman grading system provides further prognostic information.

Materials And Methods: We studied the pathological features and cancer specific survival of 237 patients with clear cell cancer undergoing surgery between 1997-2007 in a single centre. The original Fuhrman grading system was investigated as well as various simplified models utilising the original Fuhrman grade.

Results: The median follow up was 69 months. On univariate analysis, the conventional Fuhrman grading system as well various simplified models were predicative of cancer specific survival. On multivariate analysis, only the three tiered modified model in which grades 1 and 2 were combined whilst grades 3 and 4 were kept separate was an independent predictor of cancer specific survival (p=0.001, HR 2.17, 95% CI 1.37-3.43). Furthermore this simplified model demonstrated a stronger relationship to recurrence than the conventional 4 tiered Fuhrman grading system.

Conclusions: A modified, three-tiered Fuhrman grading system has been demonstrated to be an independent predictor of cancer specific survival.
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September 2013

The epidemiology and risk factors for renal cancer.

Curr Urol 2013 Feb 8;6(4):169-74. Epub 2013 Feb 8.

Unit of Experimental Therapeutics, Institute of Cancer, College of MVLS, University of Glasgow, Western Infirmary, UK.

Background: Renal cancer is a frequently occurring malignancy with over 270,000 new cases diagnosed and it being responsible for 110,000 deaths annually on a global basis. Incidence rates have gradually increased whilst mortality rates are starting to plateau.

Objective: To review epidemiology and risk factors for renal cancer.

Methods: The current data is based on a thorough review of available original and review articles on epidemiology and risk factors for renal cancer with a systemic literature search utilising Medline.

Results: The prevalence of associated risk factors such as genetic susceptibility, smoking, hypertension and obesity are changing and could account for the changes in incidence whilst the role of diet and occupational exposure to carcinogens requires further investigation.

Conclusion: Despite the evidence of various associated risk factors, further work is required from well designed studies to gain a greater understanding of the etiology of renal cancer.
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February 2013

Does surgery have a role in management of chronic intrascrotal pain?

Urology 2008 Jun 24;71(6):1099-102. Epub 2008 Apr 24.

Department of Urology, Gartnavel General Hospital, Glasgow, United Kingdom.

Objectives: To assess the role of epididymectomy in the treatment of chronic postvasectomy and epididymal pain syndrome and to identify the factors that predict the outcome.

Methods: A total of 38 patients, aged 20 to 70 years (mean 45), who had undergone epididymectomy for intractable intrascrotal pain, were identified retrospectively from the pathology records. The clinical notes were reviewed, and details on patient demographics, previous vasectomy, investigations, and histologic features were collected and analyzed. The outcome was assessed by routine outpatient clinic review and telephone interview.

Results: Overall, 32% of patients reported resolution of symptoms after epididymectomy; 17 patients had undergone previous vasectomy, and this group was significantly more likely to have ongoing pain. Abnormal examination and ultrasound findings preoperatively did not correlate with a better outcome from surgery.

Conclusions: The results of our study have shown that epididymectomy has a limited role in the management of chronic intrascrotal pain.
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June 2008

Acute urinary retention: what is the impact on patients' quality of life?

BJU Int 2005 Jan;95(1):72-6

Urology Department, St George's Hospital, London, UK.

Objective: To evaluate the impact of admission for acute urinary retention (AUR) on patients' health-related quality of life (HRQoL) compared with that on admission for elective surgery for benign prostatic hyperplasia (BPH) and emergency admission for renal colic (RC).

Patients And Methods: Over a 2-year period, three groups of men were recruited from one institution: group 1, men aged >50 years presenting to the accident and emergency (A&E) department with AUR; group 2, for comparison, men aged >50 years admitted for elective surgery for BPH; and group 3, men aged >40 years presenting to A&E with RC. A self-completed HRQoL questionnaire was administered at five visits (72 h from admission, and 1, 2, 3 and 6 months afterward) over a 6-month follow-up.

Results: Group 1 reported mean pain scores on admission of 7.7, compared with 5.6 for group 2 and 8.3 for group 3. Patients in group 1 had the most investigations and recurrent attendance to A&E throughout the study, compared with almost none for the other two groups. There was a substantial economic burden for group 1; 15% had extra help at home at a mean cost of 403 UK pounds for the duration of the study. For the other domains assessed (e.g. emotions, mental state, general health) groups 1 and 2 were similar.

Conclusions: An episode of AUR has a measurable impact on patients' HRQoL, which often occurs in the community and therefore may not be appreciated by the urology team providing their care. Further work is therefore required to improve the "patient journey" for those with AUR, and to prevent patients developing AUR in the future.
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January 2005

Zoledronic acid induces apoptosis and inhibits adhesion to mineralized matrix in prostate cancer cells via inhibition of protein prenylation.

BJU Int 2004 Jul;94(1):164-70

Department of Urology, St George's Hospital, London, UK.

Objective: To investigate effects of zoledronic acid on apoptosis and adhesion to mineralized matrix in prostate cancer cells, to quantify these actions, and to elucidate some of the underlying molecular mechanisms, in terms of dependence on caspase activation and involvement of protein prenylation.

Materials And Methods: DU145 and PC-3 prostate cancer cell lines were used; cells were treated with zoledronic acid, with or without several other reagents, to investigate its mechanism of action. Apoptosis was detected using a cell-death detection enzyme-linked immunosorbent assay. Adhesion was measured by seeding cells onto mineralized dentine inserts for 24 h, and counting cells after washing.

Results: Apoptosis depended on time and dose; there was significant apoptosis with higher concentrations of zoledronic acid (100 micromol/L) after 24 h of exposure, and in DU145 cells with concentrations as low as 1 micromol/L after 72 h of exposure. The apoptotic effect was diminished by co-treating with a broad-spectrum caspase inhibitor, Z-VAD-FMK. Zoledronic acid at 1 micromol/L also significantly inhibited cell adhesion to the mineralized matrix. The lipid isoprenoid analogue geranylgeraniol reduced the apoptotic and anti-adhesive effects of zoledronic acid to a greater degree than farnesol. There was also apoptosis and inhibition of adhesion with direct inhibitors of prenylation, e.g. manumycin A and GGTI-298. C3 exoenzyme, an inhibitor of RhoA, inhibited adhesion but did not cause apoptosis.

Conclusion: Zoledronic acid induces apoptosis in prostate cancer cells via a caspase-dependent mechanism, and at concentrations as low as 1 micromol/L it also inhibits adhesion of cells to mineralized matrix. These effects appear to be exerted via inhibiting G-protein prenylation and in particular geranylgeranylation.
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July 2004

Nitrogen containing bisphosphonates induce apoptosis and inhibit the mevalonate pathway, impairing Ras membrane localization in prostate cancer cells.

J Urol 2003 Jul;170(1):246-52

Department of Urology, St. George's Hospital and Medical School, First Floor, Ingleby House, Blackshaw Road, London SW17 0QT, UK.

Purpose: Metastasis to bone is an important cause of morbidity in advanced prostate cancer. Despite the typically sclerotic nature of prostatic bone metastases osteolysis has a significant role in the pathogenesis of this disease. The nitrogen containing bisphosphonates (N-BPs), such as pamidronate and zoledronic acid, have greatly enhanced potency for inhibiting bone resorption and inducing apoptosis in osteoclasts. We investigated the effects of N-BPs on prostate cancer cells.

Materials And Methods: Cell viability was determined with an MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymeyhoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) dye reduction assay. Cell cycle analysis, DNA fragmentation and caspase 3 activity were assessed using flow cytometry. Ras, Bcl-2 and Bax were quantified by Western blotting.

Results: Pamidronate and zoledronic acid decreased cell viability in the 3 human cell lines DU145, PC3 and LNCaP. These effects were associated with changes in cell cycle distribution, induction of DNA fragmentation and a decrease in the Bcl-2-to-Bax ratio, which are features of apoptotic cell death. Pre-incubation with caspase inhibitors attenuated the effects of zoledronic acid and caspase 3 activity was demonstrated in treated DU145 cells. Zoledronic acid induced loss of cell viability in DU145 cells was prevented by co-treatment with farnesol, suggesting that N-BPs cause inhibition of the mevalonate pathway and Ras prenylation. A decrease in active, membrane bound Ras in zoledronic acid treated DU145 cells was shown by Western blot analysis.

Conclusions: N-BPs induce apoptosis in prostate cancer via a caspase dependent mechanism. They have effects on protein prenylation via inhibition of the mevalonate pathway and impair membrane localization of Ras in prostate cancer cells.
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July 2003