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ABSTRACT: The development of androgen independence, chemo-, and radioresistance are critical markers of prostate cancer progression and the predominant reasons for its high mortality. Understanding the resistance to therapy could aid the development of more effective treatments.
The aim of this study is to investigate the effects of insulin-like growth factor-binding protein-2 (IGFBP-2) on prostate cancer cell proliferation and its effects on the response to docetaxel.
DU145 and PC3 cells were treated with IGFBP-2, insulin-like growth factor I (IGF-I) alone or in combination with blockade of the IGF-I receptor or integrin receptors. Cells were also treated with IGFBP-2 short interfering ribonucleic acid with or without a PTEN (phosphatase and tensin homologue deleted on chromosome 10) inhibitor or docetaxel. Tritiated thymidine incorporation was used to measure cell proliferation and Trypan blue cell counting for cell death. Levels of IGFBP-2 mRNA were measured using RT-PCR. Abundance and phosphorylation of proteins were assessed using western immunoblotting.
The IGFBP-2 promoted cell growth in both cell lines but with PC3 cells this was in an IGF-dependent manner, whereas with DU145 cells the effect was independent of IGF receptor activation. This IGF-independent effect of IGFBP-2 was mediated by interaction with β-1-containing integrins and a consequent increase in PTEN phosphorylation. We also determined that silencing IGFBP-2 in both cell lines increased the sensitivity of the cells to docetaxel.
The IGFBP-2 has a key role in the growth of prostate cancer cells, and silencing IGFBP-2 expression reduced the resistance of these cells to docetaxel. Targeting IGFBP-2 may increase the efficacy of docetaxel.
British Journal of Cancer 05/2011; 104(10):1587-93. · 5.04 Impact Factor
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ABSTRACT: A substantial proportion of patients who have undergone a radical prostatectomy for localised prostate cancer will have either persistently detectable prostate-specific antigen (PSA) levels or a delayed rise in PSA. The optimum treatment for these situations is not known. The key question is whether the PSA is reflective of local or distant progression. For salvage radiotherapy to be most effective, treatment should be considered before the PSA level is allowed to rise too high, when disease is more likely to be confined to the prostate bed. However, at low PSA levels, current imaging techniques are poor at detecting disease, making it difficult to differentiate local and distant recurrences and to target the radiotherapy appropriately. We review current and investigational imaging techniques, including bone scan, computed tomography, magnetic resonance imaging, positron emission tomography and Prostascint, assessing their utility in the situation of biochemical recurrence after radical prostatectomy.
Clinical Oncology 11/2009; 22(1):46-55. · 2.07 Impact Factor
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S Evans,
C Metcalfe,
B Patel,
F Ibrahim,
K Anson,
F Chinegwundoh,
C Corbishley, D Gillatt,
R Kirby,
G Muir,
V Nargund,
R Popert,
P Wilson,
R Persad,
Y Ben-Shlomo
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ABSTRACT: In the United States, Black men have a higher risk of prostate cancer and worse survival than do White men, but it is unclear whether this is because of differences in diagnosis and management. We re-examined these differences in the United Kingdom, where health care is free and unlikely to vary by socioeconomic status.
This study is a population-based retrospective cohort study of men diagnosed with prostate cancer with data on ethnicity, prognostic factors, and clinical care. A Delphi panel considered the appropriateness of investigations and treatments received.
At diagnosis, Black men had similar clinical stage and Gleason scores but higher age-adjusted prostate-specific antigen levels (geometric mean ratio 1.41, 95% confidence interval (95% CI): 1.15-1.73). Black men underwent more investigations and were more likely to undergo radical treatment, although this was largely explained by their younger age. Even after age adjustment, Black men were more likely to undergo a bone scan (odds ratio 1.37, 95% CI: 1.05-1.80). The Delphi analysis did not suggest differential management by ethnicity.
This UK-based study comparing Black men with White men found no evidence of differences in disease characteristics at the time of prostate cancer diagnosis, nor of under-investigation or under-treatment in Black men.
British Journal of Cancer 11/2009; 102(2):249-54. · 5.04 Impact Factor
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C Metcalfe,
S Evans,
F Ibrahim,
B Patel,
K Anson,
F Chinegwundoh,
C Corbishley, D Gillatt,
R Kirby,
G Muir,
V Nargund,
R Popert,
R Persad,
Y Ben-Shlomo
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ABSTRACT: Black men in England have three times the age-adjusted incidence of diagnosed prostate cancer as compared with their White counterparts. This population-based retrospective cohort study is the first UK-based investigation of whether access to diagnostic services underlies the association between race and prostate cancer. Prostate cancer was ascertained using multiple sources including hospital records. Race and factors that may influence prostate cancer diagnosis were assessed by questionnaire and hospital records review. We found that Black men were diagnosed an average of 5.1 years younger as compared with White men (P<0.001). Men of both races were comparable in their knowledge of prostate cancer, in the delays reported before presentation, and in their experience of co-morbidity and symptoms. Black men were more likely to be referred for diagnostic investigation by a hospital department (P=0.013), although general practitioners referred the large majority of men. Prostate-specific antigen levels were comparable at diagnosis, although Black men had higher levels when compared with same-age White men (P<0.001). In conclusion, we found no evidence of Black men having poorer access to diagnostic services. Differences in the run-up to diagnosis are modest and seem insufficient to explain the higher rate of prostate cancer diagnosis in Black men.
British Journal of Cancer 10/2008; 99(7):1040-5. · 5.04 Impact Factor
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Es Rennel,
E Waine,
H Guan,
Y Schüler,
W Leenders,
J Woolard,
M Sugiono, D Gillatt,
Es Kleinerman,
Do Bates,
Sj Harper
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ABSTRACT: Vascular endothelial growth factor-A is widely regarded as the principal stimulator of angiogenesis required for tumour growth. VEGF is generated as multiple isoforms of two families, the pro-angiogenic family generated by proximal splice site selection in the terminal exon, termed VEGFxxx, and the anti-angiogenic family formed by distal splice site selection in the terminal exon, termed VEGFxxxb, where xxx is the amino acid number. The most studied isoforms, VEGF165 and VEGF165b have been shown to be present in tumour and normal tissues respectively. VEGF165b has been shown to inhibit VEGF- and hypoxia-induced angiogenesis, and VEGF-induced cell migration and proliferation in vitro. Here we show that overexpression of VEGF165b by tumour cells inhibits the growth of prostate carcinoma, Ewing's sarcoma and renal cell carcinoma in xenografted mouse tumour models. Moreover, VEGF165b overexpression inhibited tumour cell-mediated migration and proliferation of endothelial cells. These data show that overexpression of VEGF165b can inhibit growth of multiple tumour types in vivo indicating that VEGF165b has potential as an anti-angiogenic, anti-tumour strategy in a number of different tumour types, either by control of VEGF165b expression by regulation of splicing, overexpression of VEGF165b, or therapeutic delivery of VEGF165b to tumours.
British Journal of Cancer 05/2008; 98(7):1250-7. · 5.04 Impact Factor
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ABSTRACT: Nutritional support has been demonstrated to improve recovery from radical cystectomy, but is expensive and when used inappropriately may actually increase the costs and morbidity of surgery. We sought to establish national patterns of practice with regard to feeding following cystectomy in the UK.
Following consultation with the specialist nutrition team, a questionnaire was designed to investigate the feeding strategy after cystectomy and dispatched by post to all UK urologists.
The majority (60%) of respondents employed a traditional strategy of resting the bowel and feeding orally after bowel recovery. A minority used either early total parenteral nutrition (TPN; 18.5%) or enteral nutrition (6.5%), but a larger proportion (29%) felt enteral nutrition was the 'optimal' feeding regime. Only 30% used guidelines and 52% felt trials would help to establish a nutrition strategy following cystectomy.
There is little evidence that TPN improves the outcome of cystectomy and it may actually increase morbidity and costs, whereas enteral nutrition may improve recovery. Despite this evidence TPN is widely used by urologists whereas enteral nutrition is used infrequently. Implementation of an evidence-based feeding regime after cystectomy is likely to reduce the morbidity and financial costs of cystectomy.
Urologia Internationalis 02/2006; 77(2):139-42. · 0.99 Impact Factor
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ABSTRACT: Tall people, particularly those with long legs, have an increased risk of developing cancer but a reduced risk of cardiovascular disease and type II diabetes. We examined associations of stature and body mass index with IGF-I, IGF-II, and IGF binding protein (IGFBP)-2 and IGFBP-3 in 274 men aged 50-70 yr to investigate whether variations in growth factor levels underlie associations of anthropometry with a number of adult diseases. Height and leg and trunk length were not strongly associated with circulating levels of IGF-I, IGF-II, or IGFBP-3. The molar ratio of IGF-I/IGFBP-3 increased with increases in the leg/trunk length ratio (P = 0.06). IGFBP-2 was positively associated with leg length and inversely associated with trunk length. Mean levels of IGFBP-2 (in nanograms per milliliter) across quartiles of increasing leg length were 504.4 493.6, 528.7, and 578.8 (P(trend) = 0.06), and for trunk length were 615.2, 507.2, 498.6, 488.5 (P(trend) < 0.01), suggesting that variations in IGFBP-2, or a factor influencing its levels in the circulation, may contribute to biological mechanisms underlying height-disease associations. We conclude that whereas growth-influencing exposures during childhood, which may operate through effects on IGF-I levels, have long-term influences on disease risk, they do not necessarily program IGF-I levels throughout life. The associations of anthropometry with IGFBP-2 merit additional investigation.
Journal of Clinical Endocrinology & Metabolism 02/2004; 89(1):213-8. · 6.50 Impact Factor
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BJU International 01/2004; 92 Suppl 3:e9. · 2.84 Impact Factor
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D Gunnell,
S E Oliver,
T J Peters,
J L Donovan,
R Persad,
M Maynard, D Gillatt,
A Pearce,
F C Hamdy,
D E Neal,
J M P Holly
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ABSTRACT: We examined the association of diet with insulin-like growth factors (IGF) in 344 disease-free men. Raised levels of IGF-I and/or its molar ratio with IGFBP-3 were associated with higher intakes of milk, dairy products, calcium, carbohydrate and polyunsaturated fat; lower levels with high vegetable consumption, particularly tomatoes. These patterns support the possibility that IGFs may mediate some diet-cancer associations.
British Journal of Cancer 07/2003; 88(11):1682-6. · 5.04 Impact Factor
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J Donovan,
F Hamdy,
D Neal,
T Peters,
S Oliver,
L Brindle,
D Jewell,
P Powell, D Gillatt,
D Dedman,
N Mills,
M Smith,
S Noble,
A Lane
Health technology assessment (Winchester, England) 02/2003; 7(14):1-88. · 4.26 Impact Factor
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ABSTRACT: Vascular endothelial growth factor (VEGF) is a potent promoter of endothelial mitogenesis and of endothelial permeability. Within the kidney it is synthesized primarily in the visceral glomerular epithelial cells (vGECs); however, the role of VEGF in the glomerulus remains unknown, as does the target cell upon which it acts. Although the target cells may be those of the glomerular endothelium, there are micro-anatomical reasons why this might not be the case. This, therefore, led us to consider the possibility that glomerular VEGF may bind to the vGECs themselves. Since it has been shown that vGECs do not express the main tyrosine kinase VEGF receptors, we chose to study vGEC expression of the more recently described VEGF isoform-specific receptors, the neuropilins. The expression of mRNAs for neuropilin-1, neuropilin-2 and soluble neuropilin was studied in whole kidney, sieved glomeruli and cultured podocytes by reverse transcription-PCR, and neuropilin-1 mRNA expression in isolated single glomeruli was analysed by nested reverse transcription-PCR. The expression of neuropilin-1 protein was investigated in cultured vGECs by Western blotting and immunocytochemistry, and in normal kidney sections by immunohistochemistry. Neuropilin-1 mRNA was detected in whole kidney, single and sieved glomeruli and cultured vGECs. Neuropilin-1 protein was detected in cultured vGECs and in vGECs in normal kidney sections by immunohistochemistry. Thus the present study suggests that vGECs may have the potential to bind the VEGF that they secrete. Functional studies will be required to address the potential significance of this finding in terms of an autocrine loop or VEGF sequestration.
Clinical Science 11/2001; 101(4):439-46. · 4.61 Impact Factor
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BMJ 02/1999; 318(7179):299-300. · 14.09 Impact Factor
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ABSTRACT: To report the initial results of the treatment of patients with benign prostatic hyperplasia using interstitial laser coagulation (ILC) performed with a temperature-sensing laser system.
Twenty-five patients were treated using ILC and in 12, 78 temperature-power curves were recorded. The aim of the treatment was to maintain a temperature of 100 degrees C during the entire treatment cycle, using the temperature-triggered feed-back system. The time to reach the maximum temperature, the maximum temperature and the energy delivered were related to the location of the punctures within the prostate. The clinical outcome at 1 and 3 months was evaluated with symptom scores and uroflowmetry variables.
Heating at the apex seemed to require less energy to achieve and maintain higher temperatures than heating of the median lobe or base of the prostate. Patients improved markedly 1 and 3 months after treatment; the respective mean symptom scores improved from 20.6 before treatment to 9.4 and 6.9, the maximum urinary flow rates from 9.1 mL/s to 14.1 mL/s and 20.3 mL/s and the post-void residual volume decreased significantly from 71 mL to 31 mL and 11 mL. No significant complications (incontinence, impotence or haemorrhage requiring transfusion) occurred.
The energy needed to achieve coagulation differed at sites within the prostate, depending on local circumstances. Good results were obtained using the tissue-adaptive laser system.
British Journal of Urology 10/1997; 80(3):433-8.
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ABSTRACT: The incidence of prostate cancer is rising worldwide, caused mainly by demographic factors, particularly the increasingly elderly population and, more importantly, the increasing number of cases identified following prostate specific antigen (PSA) testing. It is commonly quoted that many more men die with prostate cancer than of it. Autopsy/post-mortem studies show that while a very high proportion of elderly men have histological evidence of the disease, a much smaller proportion develop clinically apparent cancer. The natural history of prostate cancer is poorly understood, but progression appears to be related to stage and grade of tumour. Prostate cancer can be diagnosed by digital rectal examination (DRE), serum PSA test, and/or transrectal ultrasound (TRUS), with confirmation by biopsy. Each test identifies a proportion of cancers, with higher rates of detection when they are used in combination. The tests are also used to determine which tumours are localised within the prostate and are, thus, potentially treatable. Unfortunately, clinical staging is unreliable, with approximately one half of all tumours upstaged following surgery. Three major treatment options are available for localised prostate cancer: radical prostatectomy, radical radiotherapy and conservative management (involving monitoring and treatment of symptoms). Although radical treatment rates are rising, good quality evidence concerning their comparative effectiveness and cost-effectiveness is lacking. Observational studies of highly selected patient groups suggests that there may be a slightly lower mortality rate following radical treatments compared with conservative management, but there has been very little research into treatment complications and quality of life of men after any of the treatments. In the past, investigations of prostate cancer were reserved largely for patients exhibiting symptoms, but the introduction of the PSA test has opened up the possibility of screening healthy men for the disease. Observational studies suggest that DRE and PSA, combined with TRUS and biopsy, can identify localised prostate cancer in 3-5% of men, although the tests do result in a number of false positives and negatives. Major questions remain concerning the natural history of the disease, potential costs (financial, social and psychological) of a screening programme, and the effectiveness and cost-effectiveness of treatments for localised disease. The lack of good quality data and the strength of these concerns means that population screening for prostate cancer cannot be recommended.
Health technology assessment (Winchester, England) 02/1997; 1(2):i, 1-96. · 4.26 Impact Factor
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ABSTRACT: To report the initial results of treatment of outlet obstruction induced by benign prostatic hyperplasia (BPH) using interstitial laser coagulation performed with the Indigo 830 nm diode laser system.
A group of 112 men with lower urinary tract symptoms caused by BPH underwent treatment with the Indigo 830 nm laser system between October 1994 and November 1995. Patients were assessed prior to treatment and at specified post-treatment intervals for symptom score, uroflow, postvoid residual, and prostate volume. Adverse events and changes in laboratory parameters were monitored at each post-treatment visit to investigate safety of the procedure.
Symptom score decreased from 20.9 at initial measurement to 9.6 at 3 months after procedure and 7.9 at 6 months. Uroflow rate increased from 8.0 mL/s initially to 15.2 and 14.2 mL/s at 3 and 6 months, respectively. Residual bladder volumes decreased from 105 mL initially to 59 and 38 mL at 3 and 6 months, respectively. There were no major complications (impotence, sustained incontinence, significant blood loss). Minor complications occurred in a small number of patients but were generally associated with urinary tract infection in patients with catheters. Three patients (2.7%) required retreatment and underwent transurethral resection of the prostate.
Interstitial laser coagulation using an 830-nm diode laser system appears to be a promising new treatment, with substantial improvements in objective and subjective parameters of obstruction and a favorable side-effect profile.
Urology 09/1996; 48(2):223-8. · 2.43 Impact Factor
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ABSTRACT: To analyse the prognostic significance of pre- and post-treatment serum prostate-specific antigen (PSA) levels, together with a variety of other factors, in a multivariable analysis of survival in men with stage D2 prostate cancer.
Cox's proportional hazards model was used to compare survival in 134 men with stage D2 metastatic prostate cancer followed prospectively over a 4 year period, using both univariable and multivariable models. The influence of the following factors on survival was analysed: pre- and post-treatment PSA (both absolute and percentage values), age, treatment, testosterone, pre- and post-treatment alkaline phosphatase (absolute and percentage values), acid phosphatase, haemoglobin, symptom score and performance status and extent of disease on bone scan.
Pre-treatment PSA levels did not significantly influence survival. Similarly, a low absolute post-treatment PSA level at 3 months after the start of treatment conferred no survival advantage relative to patients with a high PSA level at this time. A post-treatment percentage PSA of < 10% at 2, 3 and 6 months after commencement of treatment was associated with prolonged survival. Low pre-treatment alkaline phosphatase (less than the upper limit of normal) and high pre-treatment testosterone levels (> or = 10 nmol/L) were similarly associated with prolonged survival.
The strong influence of post-treatment percentage PSA on survival in patients with stage D2 prostate cancer suggests that the percentage change in bulk of metastatic deposits is more important in determining survival than the absolute volume of tumour. Pre-treatment alkaline phosphatase seems to be a better indicator of tumour activity than pre-treatment PSA. These findings have important implications for the design and analysis of clinical trials of new therapies in men with stage D2 prostate cancer and for the future selection of alternative treatments for patients with this stage of the disease.
British Journal of Urology 05/1995; 75(4):507-15.
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ABSTRACT: To compare the relative sensitivity and specificity of prostate-specific antigen (PSA) as a test for prostate cancer over a range of PSA values in a variety of patient groups, and to compare the sensitivity and specificity of PSA and prostatic acid phosphatase (PAP).
Receiver operating characteristic (ROC) curves (sensitivity plotted against 1-specificity) were constructed to compare the ability of PSA to discriminate men with prostate cancer (n = 257) from those with benign prostatic hyperplasia (BPH) (n = 220) or control patients (n = 164). Receiver operating characteristic curves were also constructed to compare PSA and PAP in 173 men with either BPH or prostate cancer.
When patients with symptomatic BPH and those with advanced prostate cancer are excluded, a PSA of 8 ng/mL has a sensitivity of 94% and a specificity of 98% for prostate cancer. In patients presenting with symptoms suggestive of bladder outflow obstruction, PSA remains a sensitive marker for prostate cancer (93% sensitivity at 10 ng/mL) but its specificity (65%) is poor. PSA is a sensitive test for skeletal metastases but levels of 60-80 ng/mL are required to achieve a specificity of 70% or more. The sensitivity of PSA is far superior to that of PAP.
Serum PSA provides good discrimination between patients with and without prostate cancer. The sensitivity and specificity of PSA can be improved by excluding men with symptomatic BPH. The specificity of PSA as a diagnostic test for prostate cancer is reduced in men with symptoms of bladder outflow obstruction. For reasonable sensitivity and specificity, a PSA of 60-80 ng/mL is required for differentiating non-metastatic from metastatic prostate cancer. The ROC curve comparing PSA and PAP provides a graphical demonstration of the superiority of PSA as a tumour marker. The ability of PSA to identify prostate cancer can be improved by selecting out groups of patients and by adjusting the cut-off level of PSA to the population under study.
British Journal of Urology 04/1995; 75(3):341-6.
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ABSTRACT: Magnetic resonance imaging (MRI) scans were performed on 55 bladder cancer patients on whom clinicopathological staging was available from transurethral resection and cystectomy specimens. The overall accuracy of MRI scanning in this group was 84%, although true concordance rates are debatable without open surgical correlation. In the subgroup of 25 patients who had accurate open surgical correlation (from cystectomy, laparotomy or post mortem) the concordance rate was 76% with MRI. Errors occurred mainly in the T3 group of tumours, with 2 being overstaged and 2 being understaged out of a total of 12 in the open surgical correlation group (66% accuracy). Difficulties were also encountered in staging tumours at the bladder base, with an error rate of 22% (2 of 9) for T4 tumours in this area. With regard to lymph node staging there was a 100% (5 of 5) specificity in defining pathologically involved nodes but there was a false negative rate of 15% (3 of 19). Although it has many advantages over CT scanning, MRI produces a significant error rate in terms of over- and under-staging invasive tumours. There are difficulties associated with detecting minimal involvement of adjacent organs and lymph nodes as well as determining the exact depth of muscle penetration. Improvements may come in the future with the use of contrast enhancement agents such as gadolinium as well as more advanced machines.
British Journal of Urology 06/1993; 71(5):566-73.
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ABSTRACT: High-dose intravenous estrogen therapy was shown to be effective in relieving bone pain due to metastatic disease in 22 of 29 (75.9%) men with advanced hormone-resistant prostate cancer. This clinical response was accompanied by significant falls in serum prostate-specific antigen (PSA) levels in 13 (44.8%) patients. It is suggested that this clinical benefit is due to a direct inhibitory effect of estrogen on prostate cancer cells.
Urology 10/1989; 34(3):134-8. · 2.43 Impact Factor
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ABSTRACT: Higher circulating levels of IGF-I have been associated with increased risk of prostate and some other cancers. Most research on prostate cancer has been based on men with symptoms or identified following treatment of benign disease. However, increasing numbers of cancer cases are now detected in asymptomatic men following prostate-specific antigen (PSA) tests. We therefore used a population-based case-finding exercise using the PSA test to examine whether associations between the IGF axis and cancer risk were apparent in this population. A matched case-control study was conducted among 7,383 men (50-70 years) receiving a PSA test as part of a case-finding exercise. Assays of IGF-I, IGF-II, IGFBP-2 and IGFBP-3 were performed on cases and 2 controls matched on age, recruitment center and calendar time. Analyses were based on 176 cases and 324 matched controls. The risk of prostate cancer increased across quartiles of IGF-I (highest vs. lowest quartile, OR = 2.34; 95% CI = 1.26-4.34; ptrend = 0.02) and IGF-II (OR = 1.78; 95% CI = 0.94-3.15; ptrend = 0.09). Controlling for smoking history and IGFBP-3 strengthened associations with cancer for both IGF-I (OR = 3.00; 95% CI = 1.50-6.01; ptrend 0.005) and IGF-II (OR = 2.02; 95% CI = 1.07-3.84; ptrend = 0.04) Associations between the IGFs and cancer risk were stronger for advanced cases. Our findings suggest that both IGF-I and IGF-II are associated with an increased risk of screen-detected prostate cancer.
