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PubMed2004

Dutasteride, the dual 5alpha-reductase inhibitor, inhibits androgen action and promotes cell death in the LNCaP prostate cancer cell line.

BACKGROUND: Reduction of T to DHT by 5alphaR in the prostate enhances androgenic activity for most targets. Inhibition of 5alphaR activity with finasteride attenuates androgen action in men and animal models. The objective of this study was to compare and contrast the effects of a potent new 5alphaR inhibitor, dutasteride, with finasteride in the LNCaP prostate cancer cell line. METHODS: LNCaP cells were incubated for varying times with T or DHT in steroid-free medium in the absence or presence of increasing doses of dutasteride or finasteride and the effects on 5alphaR activity, PSA accumulation in the medium, and on cell proliferation were determined. Drug effects on apoptosis were investigated using Annexin V staining and a cell death ELISA assay. Effects of the drugs on AR ligand-binding activity and on AR protein levels were determined. RESULTS: Dutasteride inhibited (3)H-T conversion to (3)H-DHT and, as anticipated, inhibited T-induced secretion of PSA and proliferation. However the drug also inhibited DHT-induced PSA secretion and cell proliferation (IC(50) approximately 1 microM). Finasteride also inhibited DHT action but was less potent than dutasteride. Dutasteride competed for binding the LNCaP cell AR with an IC(50) approximately 1.5 microM. High concentrations of dutasteride (10-50 microM), but not finasteride, in steroid-free medium, resulted in enhanced cell death, possibly by apoptosis. This was accompanied by loss of AR protein and decreased AR ligand-binding activity. Occupation of AR by R1881 partly protected against cell death and loss of AR protein. PC-3 prostate cancer cells, which do not contain AR, also were killed by high concentrations of dutasteride, as well as by 50 microM finasteride. CONCLUSIONS: Dutasteride exhibited some inhibitory actions in LNCaP cells possibly related to 5alphaR inhibition but also had antiandrogenic effects at relatively low concentrations and cell death-promoting effects at higher concentrations. Finasteride also was antiandrogenic, but less than dutasteride. The antiandrogenic effects may be mediated by the mutant LNCaP cell AR. Promotion of cell death by dutasteride can be blocked, but only in part, by androgens.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2003

Safety and tolerability of the dual 5alpha-reductase inhibitor dutasteride in the treatment of benign prostatic hyperplasia.

OBJECTIVE: The objective of this paper is to examine safety and tolerability data from a number of recently completed clinical trials with the novel, dual 5alpha-reductase inhibitor, dutasteride. METHODS: Intent-to-treat analyses were conducted on data for dutasteride 0.5 mg/day for drug-related adverse events, clinical laboratory test results, and prostate-specific antigen (PSA) levels derived from four large, randomised, double-blind clinical trials (n=5655). Further data were derived from a randomised, double-blind combination study of dutasteride 0.5 mg/day and tamsulosin 0.4 mg/day (n=327), and several safety studies conducted in healthy volunteers. RESULTS: Data from two-year blinded clinical studies demonstrate that dutasteride is well tolerated, with a profile comparable with that of placebo. The exception is a modestly elevated incidence of impotence, decreased libido, ejaculation disorders, and gynaecomastia. Clinical laboratory test abnormalities were reported by <1% of patients treated with dutasteride, and abnormal values occurred with similar frequency versus placebo-treated patients. In a healthy volunteer study, when dutasteride was administered daily for 1 year, it did not significantly affect bone metabolism markers, bone mineral density or lipid profiles. Dutasteride reduced total serum PSA concentrations by approximately 50% following 6, 12, and 24 months of treatment but had no effect on free-to-total PSA levels. The safety profile of dutasteride did not differ from that of finasteride in a large, parallel-group, comparator trial. Additionally, when dutasteride was used in combination with an alpha(1)-blocker, the drug-related adverse event profiles were as would be expected for the individual agents. CONCLUSIONS: Considered together, these data demonstrate dutasteride to be well-tolerated.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2006

Dutasteride: a dual 5-alpha reductase inhibitor for the treatment of symptomatic benign prostatic hyperplasia.

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, safety, drug interactions, and dosing recommendations of dutasteride, a 5-alpha reductase inhibitor for benign prostatic hyperplasia (BPH). DATA SOURCES: A MEDLINE search (1966-February 2006) was conducted to extract human research data in the English language on dutasteride. Search terms included benign prostatic hyperplasia, dutasteride, and finasteride. The reference lists of articles identified through this search process, the manufacturer's Web site, and dutasteride prescribing information were also examined. STUDY SELECTION AND DATA EXTRACTION: All published studies and clinical data from the manufacturer were included, with emphasis placed on randomized, controlled trials. DATA SYNTHESIS: Dutasteride is approved for the treatment of symptomatic BPH in men with an enlarged prostate to improve urinary symptoms, reduce the risk of acute urinary retention, and reduce the need for BPH-related surgical interventions. Compared with placebo, dutasteride has been shown to significantly improve BPH symptoms, reduce the incidence of acute urinary retention and BPH-related surgery, and improve BPH-related quality of life. Few published data exist comparing dutasteride with finasteride. The most common adverse effects of dutasteride include ear, nose, and throat infection; malaise; headache; dizziness; and musculoskeletal pain. CONCLUSIONS: Clinical trials, sponsored primarily by the manufacturer, have shown dutasteride to be an effective treatment of BPH compared with placebo and to likely possess efficacy similar to that of finasteride. Further studies are needed to gain a more clear understanding of any clinically significant differences between dutasteride and finasteride.

Azasteroids↗
PubMed2006

Clinical usefulness of serum prostate specific antigen for the detection of prostate cancer is preserved in men receiving the dual 5alpha-reductase inhibitor dutasteride.

PURPOSE: We determined whether the decrease in serum PSA seen with 5alpha-reductase inhibitors affects the clinical usefulness of PSA for prostate cancer screening using data from 2 dutasteride benign prostatic hyperplasia studies. MATERIALS AND METHODS: A total of 2,802 men 50 years or older with a clinical diagnosis of benign prostatic hyperplasia, no history of prostate cancer, PSA 1.5 to 10 ng/ml, prostate volume 30 cc or greater, an American Urological Association symptom score of 12 or greater and peak urinary flow rate 15 ml per second or less were randomized to 0.5 mg dutasteride daily or matching placebo for 24 months. Increases in PSA from baseline and the maximum increase from nadir to month 24 were compared between the groups and analyzed by prostate cancer status, as determined by PSA driven biopsy and an advised cutoff of more than 4 ng/ml after doubling to correct for dutasteride treatment with sensitivity and specificity calculated for each. RESULTS: In placebo treated men without prostate cancer there was an 8.3% median increase in PSA at month 24 compared with -59.5% in those who received dutasteride, using doubled values to correct for dutasteride treatment. In those with prostate cancer these changes were 23.8% and -37.2%, respectively. Using the upper PSA limit of 4 ng/ml sensitivity for prostate cancer in men receiving dutasteride vs placebo was 0.737 vs 0.804, while specificity was 0.671 vs 0.578. Using a PSA increase from nadir of 0.8 ng/ml the sensitivity of dutasteride was 0.548 and its specificity was 0.795. CONCLUSIONS: A doubling factor is effective for maintaining the sensitivity and specificity of PSA for prostate cancer detection in men on dutasteride. Increases in serum PSA in men receiving dutasteride should be considered suspicious and serial PSA measurements should be used to evaluate changes from nadir.

Aged↗
PubMed2004

Effect of dutasteride on the detection of prostate cancer in men with benign prostatic hyperplasia.

OBJECTIVES: To examine the rate of prostate cancer detection in three large randomized placebo-controlled benign prostatic hyperplasia trials of dutasteride. Dutasteride, which lowers serum dihydrotestosterone more than 93% by inhibiting type 1 and type 2 5-alpha-reductase, is effective in the treatment of benign prostatic hyperplasia. However, its effect on the development of prostate cancer is unknown. METHODS: A total of 4325 men with benign prostatic hyperplasia but without a history, or evidence, of prostate cancer, and a serum prostate-specific antigen level of 1.5 to 10 ng/mL, were randomized to 0.5 mg/day dutasteride or placebo for 24 months. The prostate cancer detection rates for subjects were determined by non-protocol-mandated biopsies, either during the double-blind phase of the study or during the first 3 months of the open-label extension. A follow-up questionnaire was administered to a subset of consenting subjects to ascertain the number, outcomes, and reasons for the prostate biopsies. RESULTS: The cumulative incidence of prostate cancer as an adverse event was significantly lower in the dutasteride versus placebo group at 24 months (1.1% versus 1.9%, P = 0.025) and 27 months (1.2% versus 2.5%, P = 0.002). There were no differences in the diagnosis rates of prostate cancer during the first 15 months, after which time the detection rate of prostate cancer increased in the placebo group and remained low in the dutasteride group. CONCLUSIONS: Prostate cancer detection was significantly lower in subjects randomized to dutasteride compared with the placebo group. These results have prompted the initiation of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study, which was designed and powered to test the hypothesis that treatment with dutasteride decreases the incidence and progression of prostate cancer.

5-alpha Reductase Inhibitors↗
PubMed2003

Improvements in benign prostatic hyperplasia-specific quality of life with dutasteride, the novel dual 5alpha-reductase inhibitor.

OBJECTIVES: To examine the effect of the dual-action 5alpha-reductase inhibitor dutasteride on benign prostatic hyperplasia (BPH)-specific health status, as measured by the BPH Impact Index (BII), and to identify baseline and treatment risk factors for those most bothered by their BPH symptoms at the end of the protocol. PATIENTS AND METHODS: Data were derived from three randomized, double-blind, placebo-controlled, 2-year studies conducted in 4325 men with lower urinary tract symptoms caused by benign prostatic enlargement. Each study comprised a 1-month single-blind placebo run-in period, followed by randomization to oral dutasteride 0.5 mg once daily or placebo for 2 years. Patients eligible for inclusion were consenting men aged >/= 50 years with moderate to severe symptoms (American Urological Symptom Index, AUA-SI, score >/= 12), a prostate volume of >/= 30 mL, a serum prostate-specific antigen (PSA) level of >/= 1.5 or < 10 ng/mL, and a maximum urinary flow rate (Qmax) of </= 15 mL/s. BII scores were recorded at baseline and each study visit. Clinically and statistically significant changes in BII scores from baseline were investigated for each study visit. Logistical regression analysis was used to assess the significance of baseline prostate volume, symptoms, BII item 3, baseline Qmax, serum dihydrotestosterone, testosterone, PSA, age and weight in predicting the BII score at 2 years. RESULTS: Dutasteride, but not placebo, resulted in clinically and statistically significant improvements in mean BII score from 6 months. Of patients with a baseline BII score of >/= 5 (greatest symptomatic burden) treatment with dutasteride improved the scores by 2.41, while the scores in placebo-treated patients only improved by 1.64. Dutasteride-treated patients with a baseline BII score of < 5 (least symptom burden) had a clinically significant improvement in health status, while placebo-treated patients deteriorated. Regression analysis showed that men with a combination of a baseline BII item-3 score of 3 (bothered a lot) and a high symptom score (AUA-SI >/= 20) were more likely to be bothered by their symptoms at the end of the study. Men receiving placebo were also more likely to be bothered at the end of the study than were those receiving dutasteride. CONCLUSIONS: Dutasteride treatment is associated with clinically significant improvements in BII score, reflecting improvements in the quality of life of men with BPH. Taken together with previously reported improvements in prostate volume, lower urinary tract symptoms and urinary flow, and diminution of the risk of acute urinary retention and the need for BPH-related surgery, dutasteride offers demonstrable efficacy in the management of BPH.

5-alpha Reductase Inhibitors↗
PubMed2004

Effect of the dual 5alpha-reductase inhibitor dutasteride on markers of tumor regression in prostate cancer.

PURPOSE: In the prostate testosterone is converted to dihydrotestosterone (DHT) by the enzymes 5alpha-reductase (5alphaR) types 1 and 2 (5alphaR1 and 5alphaR2). Suppression of DHT formation by 5alphaR inhibition may be beneficial in early treatment or prevention of prostate cancer. Although 5alphaR2 is the dominant enzyme in the prostate, evidence indicates that 5alphaR1 may be up-regulated in some prostate cancers. This suggests that dual inhibition of both isoenzymes may be more effective than suppression of 5alphaR2 alone in prostate cancer treatment or prevention. In this short-term pilot study we examined the effect of the dual 5alphaR inhibitor dutasteride on markers of tumor regression. MATERIALS AND METHODS: A total of 46 men with clinically staged T1 or T2 prostate cancer were randomized to receive 5 mg per day of placebo or dutasteride for 6 to 10 weeks before radical prostatectomy. Resected tissues were analyzed to determine the effect of dutasteride on intraprostatic androgen levels, and indices of apoptosis and microvessel density (MVD) in malignant tissue, as well as degree of atrophy in benign tissue. RESULTS: Treatment with dutasteride caused a 97% decrease in intraprostatic DHT and was associated with a trend toward increased apoptosis. In patients receiving dutasteride for 45 days or more, a significant increase in apoptosis and a trend toward decreased MVD in prostate cancer tissue was observed. Dutasteride treatment was also associated with an 18% decrease in mean benign epithelial cell width compared with placebo (p < 0.0001). CONCLUSIONS: In this pilot study dutasteride treatment resulted in almost complete suppression of intraprostatic DHT, increased apoptosis and a trend toward decreased MVD. These findings suggest that short-term treatment with dutasteride can cause regression in some prostate cancers.

5-alpha Reductase Inhibitors↗
PubMed2005

Long-term sustained improvement in symptoms of benign prostatic hyperplasia with the dual 5alpha-reductase inhibitor dutasteride: results of 4-year studies.

OBJECTIVE: To report additional analyses of efficacy over the initial 2 years and during a 2-year open-label extension of the three pivotal phase 3 studies in which dutasteride, a dual inhibitor of type 1 and 2 5alpha-reductase, was shown to be effective and well tolerated. PATIENTS AND METHODS: All patients in the placebo and active groups were eligible for entry into the 2-year open-label extension, with all receiving dutasteride 0.5 mg daily. Mean changes from baseline were calculated for the American Urologic Association Symptom Index (AUA-SI) score at each scheduled time in the double-blind and open-label phase. The additional analyses included a breakdown of the AUA-SI score, including stratifying patients by symptom severity, assessment by baseline age and prostate volume, and the evaluation of symptoms responders. RESULTS: There was a clinically meaningful improvement in AUA-SI in patients on dutasteride in the double-blind phase, but not in those on placebo. At 48 months, patients on dutasteride in both study phases had greater improvements in AUA-SI score and individual question scores than those on dutasteride in the open-label phase only. The proportion of patients with severe symptoms declined in both study groups, although these changes were more profound in those receiving dutasteride for the 4-year duration of the study. CONCLUSION: In men with symptomatic benign prostatic hyperplasia, long-term (4-year) treatment with the dual isozyme 5alpha-reductase inhibitor dutasteride resulted in sustained and continued improvements in symptoms and flow rate. For 4 vs 2 years, longer dutasteride therapy resulted in greater symptom improvement.

5-alpha Reductase Inhibitors↗
PubMed2004

Efficacy and safety of long-term treatment with the dual 5 alpha-reductase inhibitor dutasteride in men with symptomatic benign prostatic hyperplasia.

OBJECTIVES: Dutasteride, a dual inhibitor of Type 1 and Type 2 5 alpha-reductase, has been shown to improve disease measures in patients with symptomatic benign prostatic hyperplasia (BPH) in three randomised, placebo-controlled, large-scale, 2-year Phase III clinical studies. This paper reports the pooled results of a 2-year open-label extension of the three randomised studies assessing the long-term efficacy and safety of dutasteride. METHODS: Patients randomised to dutasteride or placebo in the double-blind portion of the Phase III studies were eligible for a 2-year open-label extension, where all patients received dutasteride 0.5mg daily (dutasteride/dutasteride [D/D] group and placebo/dutasteride [P/D group]). RESULTS: Significant improvements in AUA-SI score and Q(max) were observed from Month 24 to 48 in both study groups. At Month 48, patients in the D/D group had significantly greater improvements in AUA-SI score and Q(max), and significantly greater reductions in prostate volume, than those in the P/D group. Acute urinary retention and BPH-related surgery occurred in a small percentage of patients during the open-label phase. No new safety issues were noted with long-term therapy. Onset of new drug-related adverse events were reported most frequently at the start of therapy and declined over time in patients receiving dutasteride. CONCLUSIONS: Long-term treatment with dutasteride results in continuing improvements in urinary symptoms and flow rate, and further reductions in TPV, in men with symptomatic BPH. The reduction in risk of AUR and BPH-related surgery, seen in the double-blind phase, was durable over 4-year treatment. Dutasteride was also well tolerated in long-term use.

5-alpha Reductase Inhibitors↗
PubMed2003

Dutasteride.

Dutasteride, a potent inhibitor of type 1 and 2 5alpha-reductase, reduced dihydrotestosterone levels by >90% in 85% of patients following 1 years' administration of oral dutasteride 0.5 mg/day. A combined analysis of three placebo-controlled clinical studies conducted in patients with benign prostatic hyperplasia (BPH) found sustained improvements in American Urological Association- Symptom Index scores and urinary flow rate and a 57% decrease in the risk of acute urinary retention throughout the 2-year treatment period (all p < 0.001 vs placebo). Total prostate and transition zone volume were also reduced (both p < 0.001), as was the risk of BPH-related surgery (by 48%). A nonblind extension study found that dutasteride maintains efficacy for up to 4 years. Dutasteride monotherapy maintained symptom relief following combination treatment with dutasteride and tamsulosin in all patients but those with severe symptoms. Dutasteride was generally well tolerated. Impotence, reduced libido, gynaecomastia and ejaculation disorder occurred significantly more often in dutasteride than placebo recipients, but incidence was generally low. With the exception of gynaecomastia, incidence consistently decreased over time.

5-alpha Reductase Inhibitors↗
PubMed2003

Alpha-blocker therapy can be withdrawn in the majority of men following initial combination therapy with the dual 5alpha-reductase inhibitor dutasteride.

OBJECTIVES: The Symptom Management After Reducing Therapy (SMART-1) study examined the combination of the dual action 5alpha-reductase inhibitor (5ARI) dutasteride, and alpha(1)-blocker tamsulosin, followed by withdrawal of tamsulosin in men with symptomatic BPH. METHODS: 327 BPH patients were randomised to 0.5mg dutasteride and 0.4 mg tamsulosin for 36 weeks (DT36) or 0.5 mg dutasteride and 0.4 mg tamsulosin for 24 weeks followed by dutasteride and tamsulosin matched placebo for the remaining 12 weeks (DT24+D12). Patients' assessment of their symptoms, IPSS at weeks 24, 30, and drug safety were evaluated. RESULTS: 77% of DT24+D12 patients felt the same/better at week 30 compared with week 24 (changes in IPSS were consistent with this finding). Of those subjects with an IPSS <20 who changed to dutasteride monotherapy at week 24, 84% switched without a noticeable deterioration in their symptoms. In the 27% of men with severe baseline symptoms (IPSS >or=20) who had withdrawal of tamsulosin therapy at week 24, 42.5% reported a worsening of their symptoms compared with 14% in the DT36 group. The regimens were well tolerated. CONCLUSIONS: Dutasteride can be used in a 24-week combination with tamsulosin, to achieve rapid onset of symptom relief in patients at risk of underlying disease progression. This symptom relief is maintained in the majority of patients after the alpha(1)-blocker is removed from the combination. Patients with severe symptoms may benefit from longer-term combination therapy.

Adrenergic alpha-Antagonists↗
PubMed2006

Long-term therapy with the dual 5alpha-reductase inhibitor dutasteride is well tolerated in men with symptomatic benign prostatic hyperplasia.

OBJECTIVE: To examine the long-term (4-year) safety and tolerability of dutasteride in the treatment of symptomatic benign prostatic hyperplasia (BPH). PATIENTS AND METHODS: Patients who completed the double-blind phase of three dutasteride Phase III studies were eligible to enter a 2-year open-label extension, during which all patients received dutasteride 0.5 mg. Safety was assessed, including adverse-event reporting, clinical laboratory assessments, yearly physical examinations, and vital sign assessments. RESULTS: In all, 2340 patients entered the open-label phase, 1188 of whom previously received dutasteride during the double-blind phase of the study. The most common drug-related adverse events (occurring in > or = 1%) were effects on sexual function, which decreased with a longer duration of therapy. Gynaecomastia was reported in a small percentage of men throughout the 4-year study period. The incidence of individual sexual functional adverse events that led to withdrawal was < or = 1% (0.3-1.0%) during the 4-year study period. Dutasteride had no relevant effects on vital signs or clinical laboratory variables. CONCLUSION: These data show that dutasteride is well tolerated during long-term use for the treatment of symptomatic BPH.

5-alpha Reductase Inhibitors↗
PubMed2006

Discovery and clinical development of dutasteride, a potent dual 5alpha-reductase inhibitor.

In this review the preclinical medicinal chemistry, biochemistry and clinical results achieved in the treatment of prostatic disease with dutasteride, a dual inhibitor of type 1 and type 2,5alpha-reductase are described. During the discovery phase, dutasteride was optimized to inhibit both forms of human 5 alpha-reductase (5AR) via extensive structure activity relationship studies versus the cloned human isozymes. Dutasteride has subsequently been shown to improve disease measures in patients with symptomatic benign prostatic hyperplasia (BPH) in three randomized, placebo-controlled, Phase III clinical studies lasting for 2 years. Additionally, dutasteride is now under study for the ability to reduce the incidence of prostate cancer in men at high risk of the disease--an indication where the unique dual inhibitor nature, half-life and tolerability of dutasteride may be especially significant factors in determining treatment success. The connections between preclinical drug design and clinical outcomes during the discovery and development of dutasteride are exemplified.

Animals↗
PubMed2005

[Effect of dutasteride on reduction of plasma DHT following finasteride therapy in patients with benign prostatic hyperplasia].

INTRODUCTION: Dihydrotestosterone (DHT) is a steroid hormone derived from testosterone, by the action of two distinct isoenzymes (type 1 and 2) of 5-alpha-reductase. Dutasteride is a specific selective inhibitor of the two isoenzymes, while finasteride is a selective inhibitor of type 2 -alpha-reductase. The working hypothesis is that the double 5-alpha-reductase inhibition induced by dutasteride therapy for 6 weeks should induce a supplementary reduction of plasma DHT levels compared to a parallel patient group continuing finasteride therapy over the same period. MATERIALS AND METHODS: In this prospective, two-centre, double-blind study, 21 patients previously treated by finasteride 5 mg for benign prostatic hyperplasia (BPH) for at least 6 months were randomized to receive either dutasteride 0.5 mg, or finasteride 5 mg daily for 6 weeks. RESULTS: The mean relative variation of plasma DHT was 67.3% +/- 16.16% in the dutasteride group and 30.3% +/- 59.8% in the finasteride group. The reduction of DHT was numerically greater and more constant in the dutasteride group than in the finasteride group at 6 weeks; such a tendency was already observed after two weeks of treatment with dutasteride. Nevertheless, these differences were not statistically significant. Both medications were well tolerated and the only treatment-related adverse event (epigastric pain) was reported in the finasteride group. CONCLUSIONS: The working hypothesis was therefore not statistically confirmed. It is difficult to conclude whether this reflects poor patient compliance with long-term finasteride for BPH or variability of response in patients with good compliance with treatment.

Aged↗
PubMed2006

Effects of the dual 5 alpha-reductase inhibitor dutasteride on apoptosis in primary cultures of prostate cancer epithelial cells and cell lines.

BACKGROUND: The profound reduction in serum dihydrotestosterone (DHT) observed with the dual 5 alpha-reductase inhibitor (5ARI) dutasteride makes it an attractive agent for prostate cancer therapy. The objective of the current study was to determine whether dutasteride would induce apoptosis in a range of prostate epithelial cell lines and primary cultures. METHODS: Both human prostate androgen-sensitive cell lines (PwR-1E, PNT-2, LNCaP, and PC3[AR2]) and an androgen-independent cell line (PC-3) were grown to confluence. Primary epithelial cells extracted from fresh prostate cancer radical prostatectomy specimens also were grown to confluence under optimal conditions. Total cellular protein was extracted to confirm cytokeratin 18 and antihuman alpha-methylacyl-CoA racemase (AMACR) expression of the primary cells. Apoptosis was assessed by propidium iodide DNA staining and flow cytometry after 24 hours of culture in from 0 microM to 10 microM of dutasteride. RESULTS: Dutasteride induced a dose-dependent increase in apoptosis in the androgen-sensitive prostate cell lines PwR-1E, PNT-2, and LNCaP and in the androgen receptor-expressing PC3(AR2) cell line. However, there was no significant apoptosis noted in the parental PC-3 cells. Of 16 primary epithelial cultures that were treated, 7 cultures were induced to undergo apoptosis, and 9 cultures were unresponsive. All primary cultures were positive for cytokeratin 18 expression, confirming their epithelial phenotype. Responder epithelial cells were positive for AMACR expression. CONCLUSIONS: The results of the current study confirmed that dutasteride differentially induced apoptosis in a subset of prostate cell lines and primary prostate epithelial cells. Understanding the cellular phenotype may indicate susceptible cells.

Apoptosis↗
PubMed2004

Efficacy and safety of dutasteride in the four-year treatment of men with benign prostatic hyperplasia.

OBJECTIVES: To assess the long-term safety and efficacy of dutasteride, a dual type 1 and type 2 5-alpha-reductase inhibitor, in the treatment of symptomatic benign prostatic hyperplasia and associated lower urinary tract symptoms. METHODS: Data from two Phase IIIa multicenter, randomized, placebo-controlled trials of 2-year duration plus a 2-year open-label extension were pooled and analyzed. The entry criteria included age 50 years old or older, clinical diagnosis of benign prostatic hyperplasia, prostate volume of 30 cm3 or greater, American Urological Association symptom score of 12 or greater, peak urinary flow rate of 15 mL/s or less, and prostate-specific antigen level of 1.5 ng/mL or greater but less than 10 ng/mL. RESULTS: A total of 2802 men were randomized into the double-blind phase of the two studies with 1908 patients (68%) completing the study. Of these, 1570 subjects were enrolled in the open-label phase, and 569 subjects received dutasteride for 48 months. Changes at the 48-month visit for dutasteride/dutasteride-treated subjects included improvement in prostate volume (-26.2%), American Urological Association Symptom Index (-6.1 points), and peak urinary flow rate (+2.8 mL/s). Changes for the placebo/dutasteride group included prostate volume (-20.7%), American Urological Association Symptom Index (-5.3 points), and peak urinary flow rate (+1.8 mL/s). Acute urinary retention and surgery occurred in a small percentage of subjects (less than 2% and less than 1%) in the open-label extension phase. Dutasteride was well tolerated with no statistically significant increase in drug-related adverse events during the open-label extension and no adverse laboratory trends. CONCLUSIONS: Dual inhibition of 5-alpha-reductase with dutasteride provided sustained efficacy in subjects with symptomatic benign prostatic hyperplasia treated for 48 months. Near-complete, long-term suppression of dihydrotestosterone (93% at 48 months) with dutasteride did not lead to an increase in adverse events compared with that reported in the 2-year period.

5-alpha Reductase Inhibitors↗
PubMed2005

Chemoprevention using dutasteride: the REDUCE trial.

PURPOSE OF REVIEW: This article will review the design and rationale of the dutasteride prostate cancer chemoprevention trial known as the REDUCE trial (Reduction by Dutasteride of Prostate Cancer Events) in the context of the recently completed Prostate Cancer Prevention Trial. RECENT FINDINGS: The Prostate Cancer Prevention Trial used the 5alpha-reductase inhibitor finasteride to prevent prostate cancer in a prospective randomized trial. The trial demonstrated a nearly 25% reduction in the prevalence of prostate cancer compared with placebo. Finasteride is a type 2-specific 5alpha-reductase inhibitor, whereas dutasteride is an inhibitor of both type 1 and type 2 5alpha-reductase. Recent evidence suggests that there may be increased expression of the type 1 5alpha-reductase in prostate cancer versus benign prostate tissue making dutasteride an attractive agent to study. SUMMARY: Proof of principle has been demonstrated by the Prostate Cancer Prevention Trial that a chemoprevention strategy using a hormonal agent such as a 5alpha-reductase inhibitor can be effective. The REDUCE trial will use the dual 5alpha-reductase inhibitor dutasteride in a group of men identified at increased risk of developing prostate cancer to determine if this will be an effective chemoprevention strategy.

5-alpha Reductase Inhibitors↗
PubMed2004

Chemoprevention of prostate cancer in men at high risk: rationale and design of the reduction by dutasteride of prostate cancer events (REDUCE) trial.

PURPOSE: Chemoprevention may significantly impact the natural history of prostate cancer. The most potent intraprostatic androgen, dihydrotestosterone, has a significant role in the pathophysiology of prostate cancer. It represents a biologically plausible target for chemoprevention through the inhibition of 5alpha-reductase isoenzymes. MATERIALS AND METHODS: The Reduction by Dutasteride of Prostate Cancer Events clinical trial is an international, multicenter, double-blind, placebo controlled chemoprevention study designed to determine if dutasteride 0.5 mg daily decreases the risk of biopsy detectable prostate cancer. A total of 8,000 men will be randomized to receive dutasteride or placebo for 4 years. Eligible men must be 50 to 75 years old, have a serum prostate specific antigen of 2.5 to 10 ng/ml (ages 50 to 60 years) or 3.0 to 10 ng/ml (older than 60 years). Men must have a negative 6 to 12 core biopsy within 6 months prior to enrollment. Repeat biopsies will be taken at 2 and 4 years. The rates of prostate cancer for each treatment group will be compared. Genetic and protein biomarkers of prostate cancer, and the effect of dutasteride on benign prostatic hyperplasia and prostatitis symptomatology and histopathology will also be assessed. RESULTS: Results remain to be determined. CONCLUSIONS: The study will examine the effects of the dual 5alpha-reductase inhibitor dutasteride on the natural history of prostate cancer in men at increased risk for this malignancy. It affords a unique opportunity to examine biomarkers and genetic linkage for prostate cancer, and assess a range of prostate health outcome measures.

5-alpha Reductase Inhibitors↗