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Biomedical subjects

Martin Gleave

Publications and source records attributed to Martin Gleave.

36 records · Page 2Linked to original sources
PubMed2005

Intake of selenium in the prevention of prostate cancer: a systematic review and meta-analysis.

BACKGROUND: Recent studies have suggested that selenium intake may prevent the risk of developing prostate cancer. Results from some of these studies have given conflicting results. Because of these discrepant results we sought to explore the association between selenium intake and prostate cancer by conducting a systematic review and meta-analysis of the literature. METHODS: We systematically searched MEDLINE, EMBASE and Cochrane Library between 1966 and May 2005 for articles that examined the association between intake of selenium and the risk of prostate cancer. We abstracted the data from relevant studies. A random effects model was used to estimate pooled relative risks for both cohort and case-control studies. Heterogeneity was assessed graphically using a Funnel Plot. RESULTS: Sixteen studies (eleven cohort studies and five case-control studies) were included in the final analysis. The pooled relative risk of prostate cancer for any intake of selenium was 0.72 (0.61-0.84) for cohort studies and 0.74 (0.61-1.39) for case-control studies. The pooled relative risk of moderate intake was 0.74 (0.61-0.90) for cohort studies and 0.74 (0.39-1.39) for case-control studies. A dose-response trend was observed when we stratified the studies by disease severity. CONCLUSION: The results of our systematic review suggest that selenium intake may reduce the risk of prostate cancer. The results confirm the need for large randomized controlled trials, which are ongoing, to answer this question.

Canada↗
PubMed2005

Antisense oligonucleotide therapy in the management of bladder cancer.

PURPOSE OF REVIEW: In this paper, we will review the recent advances in antisense oligonucleotide therapy in the treatment of superficial bladder cancer. Bladder cancer has an exciting potential as a model to study antisense oligonucleotide therapy because of the ease of accessibility of treatment, ease of diagnosis through biopsy and urine cytology, and direct observation of treatment efficacy through cystoscopy and posttreatment biopsy. RECENT FINDINGS: We will elaborate on the recent developments in the delivery of antisense oligonucleotide and the implications of these results on the use of antisense oligonucleotide intravesically. We will also discuss recent preclinical in-vitro results of antisense oligonucleotide therapy in different bladder cancer cell lines. SUMMARY: Recent developments of the in-vitro and animal in-vivo effectiveness of antisense treatment in bladder cancer provide the foundation to pursue future phase I clinical trials. Antisense oligonucleotide technology is a promising tool that may become an effective method of treating bladder cancer.

Animals↗
PubMed2005

Knockdown of the cytoprotective chaperone, clusterin, chemosensitizes human breast cancer cells both in vitro and in vivo.

Clusterin is a stress-associated cytoprotective chaperone up-regulated by various apoptotic triggers in many cancers and confers treatment resistance when overexpressed. The objectives of this study were to evaluate clusterin expression levels in human breast cancer and to determine whether antisense oligonucleotides or double-stranded small interfering RNAs (siRNA) targeting the clusterin gene enhance apoptosis induced by paclitaxel. Clusterin immunostaining was evaluated in a tissue microarray of 379 spotted breast cancers. The effect of hormone withdrawal, paclitaxel treatment, clusterin antisense oligonucleotide (OGX-011), and siRNA treatments on clusterin expression was examined in MCF-7 and MDA-MB-231 cells. Northern, quantitative real-time PCR, and Western analyses were used to measure change in clusterin mRNA and protein levels. The effect of OGX-011 or siRNA clusterin treatment on chemosensitivity to paclitaxel was done in both cell lines in vitro, whereas the ability of OGX-011 to chemosensitize in vivo was evaluated in athymic mice bearing MCF-7 tumors. Clusterin was expressed in 62.5% of tumors within the tissue microarray. Clusterin expression increased after estrogen withdrawal and paclitaxel treatment in vitro in MCF-7 cells. OGX-011 or siRNA clusterin decreased clusterin levels by >90% in a dose-dependent, sequence-specific manner and significantly enhanced chemosensitivity to paclitaxel in vitro. When combined, OGX-011 or siRNA clusterin reduced the IC50 by 2-log compared with paclitaxel alone. In vivo administration of OGX-011 enhanced the effects of paclitaxel to significantly delay MCF-7 tumor growth. These data identify clusterin as a valid therapeutic target and provides preclinical proof-of-principle to test OGX-011 in multimodality therapies for breast cancer.

Adult↗
PubMed2005

Knock-down of the cytoprotective gene, clusterin, to enhance hormone and chemosensitivity in prostate and other cancers.

Discovery and targeting of genes mediating treatment resistance may lead to development of novel therapies that delay progression of recurrent and refractory cancers. Clusterin is a stress-associated cytoprotective chaperone expressed in many cancers that is upregulated in an adaptive cell survival manner by various apoptotic triggers and confers treatment resistance. Here, we review clusterin's functional role in regulating treatment-induced apoptosis and the use of a second generation antisense oligonucleotide to inhibit clusterin expression to enhance the cytotoxic effects of hormone- and chemotherapy in prostate and other xenograft models, as well as in recent human trials.

Animals↗
PubMed2005

Introduction of insulin-like growth factor binding protein-2 gene into human bladder cancer cells enhances their metastatic potential.

Overexpression of insulin-like growth factor binding protein-2 (IGFBP-2) has been shown to be associated with tumor progression in several human malignant tumors; however, the significance of IGFBP-2 expression in bladder cancer remains poorly defined. The objective of this study was to investigate the effect of IGFBP-2 overexpression in human bladder cancer KoTCC-1 cells on their phenotype associated with tumor progression. We introduced IGFBP-2 cDNA into KoTCC-1 cells, which do not express a detectable level of IGFBP-2 protein, thus generating an IGFBP-2 overexpressing cell line (KoTCC-1/BP2). We also generated a vector-only-transfected cell line (KoTCC-1/C) as a control. Despite the absence of a significant difference in in vitro cell growth rates and motilities among KoTCC-1 sublines, KoTCC-1/BP2 exhibited significantly higher invasive ability than KoTCC-1/C. Gelatin zymography showed a marked increase in matrix metalloproteinase-2 (MMP-2) production by KoTCC-1/BP2 compared with that by KoTCC-1/C. Furthermore, there was no significant difference in sub-cutaneous tumor growth among KoTCC-1 sublines; however, more advanced tumor progression, including lymph node metastasis and hemorrhagic ascites formation, was observed after the implantation of KoTCC-1/BP2 into the bladder wall of nude mice than after the implantation of KoTCC-1/C. These findings suggest that overexpression of IGFBP-2 induces an increase in MMP-2 production, resulting in the enhanced metastatic potential of bladder cancer.

Animals↗
PubMed2005

Enhanced radiosensitivity by inhibition of the anti-apoptotic gene clusterin using antisense oligodeoxynucleotide in a human bladder cancer model.

Clusterin has been shown to be implicated in the acquisition of resistant phenotype to various kinds of apoptotic stimuli, including radiation. In bladder cancer, our previous study demonstrated that overexpression of clusterin is closely associated with disease progression and recurrence. The objective of this study was to investigate whether radiation sensitivity was enhanced by suppressing clusterin gene expression with antisense (AS) oligodeoxynucleotide (ODN) in the human bladder cancer KoTCC-1 model. Clusterin mRNA in KoTCC-1 cells after radiation was up-regulated in a dose-dependent manner; however, AS clusterin ODN treatment resulted in a marked inhibition of clusterin mRNA even after irradiation. Combined treatment of KoTCC-1 cells with radiation and AS clusterin ODN synergistically decreased plating efficacy and induced apoptotic cell death compared with either radiation or AS clusterin ODN treatment alone. In vivo systemic administration of AS clusterin ODN enhanced radiation sensitivity, significantly reducing subcutaneous KoTCC-1 tumor volume in nude mice, compared with that of mismatch control ODN. Moreover, additional administration of cisplatin to this combined regimen further achieved potential antitumor effects on subcutaneous KoTCC-1 tumor growth in nude mice. Collectively, these findings suggest that clusterin acts as a cell survival protein mediating radioresistance through the inhibition of apoptosis, and that inactivation of clusterin using AS technology might offer a novel strategy to improve the outcome of radiation therapy for patients with bladder cancer.

Animals↗
PubMed2005

Enhanced expression of the secreted form of clusterin following neoadjuvant hormonal therapy as a prognostic predictor in patients undergoing radical prostatectomy for prostate cancer.

The objective of this study was to characterize changes in clusterin expression in prostate cancer before and after neoadjuvant hormonal therapy (NHT), and to assess the prognostic significance of clusterin expression following NHT in patients undergoing radical prostatectomy. Paired needle biopsy and corresponding radical prostatectomy (RP) specimens obtained from 76 patients were analyzed for expression of clusterin protein by immunohistochemical staining with an antibody recognizing all of the clusterin isoforms. RP specimens following NHT demonstrated stronger expression of clusterin than the corresponding needle biopsy specimens. Clusterin protein was present in the cytoplasm of both biopsy and RP specimens; however, there was no nuclear staining identified in any specimens. The expression level of clusterin in biopsy specimens was significantly associated with the biopsy Gleason score, but not with other parameters available before RP. Furthermore, clusterin expression in RP specimens was significantly associated with the preoperative prostate specific antigen value and pathological stage, but not with other pathological factors. Biochemical recurrence-free survival in patients with strong clusterin expression in RP specimens was significantly lower than that in those with weak clusterin expression; however, the level of clusterin expression could not be used as an independent predictor of biochemical recurrence. These findings suggest that despite the lack of independent significance, the expression level of the secreted form of clusterin in prostate cancer tissue after NHT, which may inversely reflect the therapeutic effect of NHT, could be a useful parameter predicting biochemical recurrence in patients undergoing RP.

Aged↗
PubMed2004

Heat shock protein 27 increases after androgen ablation and plays a cytoprotective role in hormone-refractory prostate cancer.

Heat shock protein 27 (Hsp27) is a chaperone implicated as an independent predictor of clinical outcome in prostate cancer. Our aim was to characterize changes in Hsp27 after androgen withdrawal and during androgen-independent progression in prostate xenografts and human prostate cancer to assess the functional significance of these changes using antisense inhibition of Hsp27. A tissue microarray was used to measure changes in Hsp27 protein expression in 232 specimens from hormone naive and posthormone-treated cancers. Hsp27 expression was low or absent in untreated human prostate cancers but increased beginning 4 weeks after androgen-ablation to become uniformly highly expressed in androgen-independent tumors. Androgen-independent human prostate cancer PC-3 cells express higher levels of Hsp27 mRNA in vitro and in vivo, compared with androgen-sensitive LNCaP cells. Phosphorothioate Hsp27 antisense oligonucleotides (ASOs) and small interference RNA potently inhibit Hsp27 expression, with increased caspase-3 cleavage and PC3 cell apoptosis and 87% decreased PC3 cell growth. Hsp27 ASO and small interference RNA also enhanced paclitaxel chemosensitivity in vitro, whereas in vivo, systemic administration of Hsp27 ASO in athymic mice decreased PC-3 tumor progression and also significantly enhanced paclitaxel chemosensitivity. These findings suggest that increased levels of Hsp27 after androgen withdrawal provide a cytoprotective role during development of androgen independence and that ASO-induced silencing can enhance apoptosis and delay tumor progression.

Androgens↗
PubMed2004

Regulation of tumor angiogenesis by integrin-linked kinase (ILK).

We show that integrin-linked kinase (ILK) stimulates the expression of VEGF by stimulating HIF-1alpha protein expression in a PKB/Akt- and mTOR/FRAP-dependent manner. In human prostate cancer cells, knockdown of ILK expression with siRNA, or inhibition of ILK activity, results in significant inhibition of HIF-1alpha and VEGF expression. In endothelial cells, VEGF stimulates ILK activity, and inhibition of ILK expression or activity results in the inhibition of VEGF-mediated endothelial cell migration, capillary formation in vitro, and angiogenesis in vivo. Inhibition of ILK activity also inhibits prostate tumor angiogenesis and suppresses tumor growth. These data demonstrate an important and essential role of ILK in two key aspects of tumor angiogenesis: VEGF expression by tumor cells and VEGF-stimulated blood vessel formation.

3-Phosphoinositide-Dependent Protein Kinases↗
PubMed2004

Hypoxia in the androgen-dependent Shionogi model for prostate cancer at three stages.

The objective of this study was to investigate a possible relationship between androgen status and hypoxia in the Shionogi murine prostate tumor model, which is widely used to study the effects of androgen withdrawal on hormone resistance and radiation response. Binding of the nitroimidazole hypoxia marker EF5 was assessed using the Cy3-tagged monoclonal antibody ELK3-51. Three hours after injection of EF5 (30 mg/kg), tumors from the following three stages were excised: androgen-dependent, regressed tumors 7 days after castration, and androgen-independent. Half of each tumor was disaggregated for analysis by flow cytometry and the remainder was flash frozen. Statistically significant differences (P < 0.01) were found between androgen-dependent, regressed and androgen-dependent tumors: approximately 30, approximately 2 and approximately 50% hypoxic cells, respectively. Frozen sections from androgen-dependent tumors exhibited highly variable EF5 binding; regressed tumors showed very little or no binding; each section from androgen-dependent tumors showed high levels and uniformly distributed binding of EF5. There was no correlation between the degree of hypoxia and tumor weight (P > 0.1). The results from this preliminary study indicate that hypoxia may play an important role with respect to the timing of irradiation in prostate cancer treatments and possibly may be a useful prognostic tool. In addition, hypoxia may also be relevant to progression in this disease after androgen ablation.

Androgens↗
PubMed2003

Safety and efficacy of vardenafil for the treatment of men with erectile dysfunction after radical retropubic prostatectomy.

PURPOSE: More than one-third of men may experience erectile dysfunction (ED) after nerve sparing radical retropubic prostatectomy. The efficacy and safety of vardenafil, a potent, selective, phosphodiesterase 5 inhibitor, was assessed for the treatment of ED after radical prostatectomy. MATERIALS AND METHODS: In this double-blind study 440 men with ED after nerve sparing radical prostatectomy were randomized to take placebo, or 10 or 20 mg vardenafil. Efficacy was measured after 12 weeks using the erectile function domain of the International Index of Erectile Function, diary questions measuring vaginal penetration and intercourse success rates, and a global assessment question (GAQ) on erection. RESULTS: Of the intent to treat population 70% had severe ED (erectile function less than 11) at baseline. After 12 weeks both vardenafil doses were significantly superior to placebo (p <0.0001) for all efficacy variables. Improved erections (based on GAQ) were reported by 65.2% and 59.4% of patients on 20 and 10 mg vardenafil, respectively, and by only 12.5% of patients on placebo (p <0.0001). Among men with bilateral neurovascular bundle sparing, positive GAQ responses were reported by 71.1% and 59.7% of patients on 20 and 10 mg vardenafil, respectively, versus 11.5% of those on placebo (p <0.0001). The average intercourse success rate per patient receiving 20 mg vardenafil was 74% in men with mild to moderate ED and 28% in men with severe ED, compared to 49% and 4% for placebo, respectively. Few adverse events were observed. They were generally mild to moderate headache, flushing and rhinitis. CONCLUSIONS: In men with severe ED after nerve sparing radical retropubic prostatectomy, vardenafil significantly improved key indices of erectile function.

Double-Blind Method↗
PubMed2003

Clusterin and IGFBPs as antisense targets in prostate cancer.

The primary hurdle to improved survival of advanced prostate cancer is our failure to prevent or treat the tumor's progression to its lethal and untreatable stage of androgen independence. Novel treatment modalities designed to prevent androgen-independent progression including prostate cancer metastasis are required. Accelerated identification and characterization of cancer-relevant molecular targets has sparked considerable interest in the development of new generations of anticancer agents that specifically inhibit a progression-relevant target. Antisense oligonucleotides, short synthetic stretches of chemically modified DNA capable of specifically hybridizing to the mRNA of a chosen cancer-relevant target gene, promise to show enhanced specificity for malignant cells with a favorable side-effect profile due to well-defined and tailored modes of action. Although not all of the challenges have been met to date, emerging clinical evidence supports the premise that antisense oligonucleotides stand a realistic chance of emerging as major partners of rationally designed anticancer regimens. The rationale and status of antisense targeting of the treatment resistance factor clusterin and of insulin-like growth factor binding protein (IGFBP) 2 and 5 are discussed.

Animals↗
PubMed2003

Antisense targets to enhance hormone and cytotoxic therapies in advanced prostate cancer.

The main obstacle to improved survival of advanced prostate cancer is our failure to prevent or treat its progression to its lethal and untreatable stage of androgen independence. New therapeutic agents designed to prevent androgen-independent progression are required. Accelerated identification and characterization of cancer-relevant molecular targets has sparked considerable interest in the development of new generations of anti-cancer agents that specifically inhibit a progression-relevant target. Antisense oligonucleotides, short synthetic stretches of chemically modified DNA capable of specifically hybridizing to the mRNA of a chosen cancer-relevant target gene. promise to show enhanced specificity for malignant cells with a more favorable side-effect profile due to well-defined and tailored modes of action. Although not all of the challenges have been met to date, emerging clinical evidence supports the premise that antisense oligonucleotides stand a realistic chance of emerging as major partners of rationally designed anti-cancer regimens. The status of antisense targeting of several genes, including bcl-2, bcl-xL, clusterin, androgen receptor and IGFBPs, relevant to prostate and other cancers, are reviewed.

Androgen Antagonists↗
PubMed2003

Intermittent androgen suppression in prostate cancer: an update of the Vancouver experience.

INTRODUCTION: This report will review the long-term follow-up of a prospective Phase II evaluation of intermittent androgen suppression in the treatment of prostate cancer. Specifically, this analysis will address completed cycle characteristics, the concept of prolonged off-treatment cycles, the time to cancer progression, cancer-specific survival and the association between PSA and bone scan changes. METHODS: A total of 102 patients have been entered into this protocol. Treatment was initiated with combined androgen blockade and continued for 6 months or longer to reach a serum PSA nadir. Medication was then withheld until the serum PSA increased to predetermined trigger points based on initial parameters. Each cycle of treatment and no-treatment was repeated until the regulation of PSA became biochemically androgen independent. RESULTS: One hundred two patients have been commenced on IAS with an average follow-up time of 219 weeks (range: 14.5 to 588). Ninety-one patients have completed at least one therapeutic cycle with a total of 188 completed cycles available for analysis. The average time off therapy (percentage time off therapy) for cycles 1, 2, 3 and 4 was 13 months (53%), 11 months (51%), 10 months (47%) and 8 months (45%), respectively. A prolonged off-treatment time of greater than 72 weeks was observed in 33 (18%) of all completed cycles, and was most common in the men being treated for radiation failure stage C. Progression and survival data was calculated for the entire trial cohort (n=102). The average time to androgen independent progression in the 29 (28%) patients who progressed was 194 weeks. Death from prostate cancer occurred in 19 (18%) patients at an average of 258 weeks following treatment initiation. A review of bone scans revealed 22 events of newly detected lesions, all but 2 of which were preceded by a rise in serum PSA. CONCLUSIONS: Longer duration follow-up of a single cohort continues to support IAS as a viable treatment option for men with prostate cancer. This approach affords an improved quality of life when the patient is off therapy, with reduced toxicity and costs. There is a trend toward extended times to progression and death compared to contemporary studies of continuous androgen suppression. Randomized, prospective protocols are currently underway to determine whether survival is affected in a beneficial or adverse way in men with locally recurrent or metastatic cancer.

Adult↗
PubMed2002

The role of antisense oligonucleotides in the treatment of bladder cancer.

Both intravesical and systemic chemotherapy are limited in their efficacy in the treatment of bladder cancer patients. These limitations are centred around an inability to induce apoptosis in bladder tumour cells. This resistance to apoptosis induction is commonly associated with the overexpression of antiapoptotic proteins such as Bcl-2. Strategies to decrease the cellular expression of such proteins would enhance chemotherapy effectiveness. One such strategy is to use antisense oligonucleotides which are short sequence specific single stranded DNA or RNA molecules designed to bind to the RNA of the target protein. By binding to the target RNA, protein production is interrupted and target protein levels decease. When used to target antiapoptotic proteins, antisense oligonucleotides can therefore be used as a pre-treatment before chemotherapy to help chemosensitise the tumour cell. This review outlines the rationale for this strategy and the work done to date with antisense oligonucleotides in bladder cancer.

Apoptosis↗
PubMed2002

Overexpression of clusterin in transitional cell carcinoma of the bladder is related to disease progression and recurrence.

OBJECTIVES: To determine whether the expression level of clusterin in transitional cell carcinoma (TCC) of the bladder could be used as a predictor of tumor recurrence and prognosis. METHODS: Total RNA samples were extracted from 89 specimens of TCC of the bladder, and the expression level of clusterin mRNA in these specimens was measured by Northern blot analysis. The results were evaluated with respect to several clinicopathologic factors. RESULTS: The mean level of clusterin mRNA expression in invasive TCC of the bladder was fourfold and fivefold higher than that in superficial TCC and normal urothelial tissue, respectively. The expression level of clusterin mRNA showed no significant correlation with sex, age, tumor size, or multiplicity, and the pathologic stage and tumor grade showed close associations with clusterin expression. The overall survival rate of patients with strong clusterin expression was significantly lower than that of patients with weak expression. Among the 43 patients with invasive TCC who underwent complete resection, the recurrence-free survival rate of patients with strong clusterin expression was significantly lower than that of patients with weak expression. Moreover, multivariate analyses indicated that among these 43 patients, strong expression of clusterin was an independent predictor of tumor recurrence. CONCLUSIONS. These findings indicate that clusterin mRNA is strongly expressed in invasive TCC of the bladder compared with the expression in superficial TCC and that strong clusterin expression could be used as a novel predictor of prognosis of patients with TCC of the bladder.

Adult↗
PubMed2002

Antisense therapy: current status in prostate cancer and other malignancies.

Recent technological advances now allowing both large scale data generation and its in-depth analysis have opened new avenues to identify and target genes involved in neoplastic transformation and tumor progression. This accelerated identification and characterization of cancer-relevant molecular targets has sparked considerable interest in the development of new generations of anti-cancer agents. It is anticipated, that these agents will show enhanced specificity for malignant cells and a more favorable side-effect profile due to well-defined and tailored modes of action. Antisense oligonucleotides (ASOs) are short synthetic stretches of chemically modified DNA capable of specifically hybridizing to the mRNA of a chosen cancer-relevant target gene are close, after decades of challenges, close to fulfilling their promise in the clinical setting. Emerging clinical evidence supports the notion that ASOs stand a realistic chance of developing into one of the main players of rationally designed anti-cancer agents, although certainly not all of the challenges have been met to date. The status of antisense targeting of genes relevant to prostate cancer, including bcl-2, bcl-xL, clusterin, androgen receptor (AR) and IGFBPs, are reviewed.

Androgen Receptor Antagonists↗