Download the Free Unbound MEDLINE PubMed App to your smartphone or tablet.
Available for iPhone, iPad, iPod touch, and Android.
- Words of wisdom. Re: Does oral antiandrogen use before leuteinizing hormone-releasing therapy in patients with metastatic prostate cancer prevent clinical consequences of a testosterone flare? Oh WK, Landrum MB, Lamont EB, et al. Urology 2010;75:642-7. [Comment, Journal Article]
- Eur Urol 2010 Aug; 58(2):314-5.
Oh et al report their experience with 1566 metastatic prostate cancer patients treated with luteinising hormone-releasing hormone (LHRH) agonists in the area of Boston, Massachusetts, USA. Of these patients, 79.5% were given antiandrogens (bicalutamide, flutamide, or nilutamide) before the first LHRH agonist dose. The remaining patients (20.5%) did not receive antiandrogens. In all patients, complications appearing within 30 d and attributable to a flare phenomenon (fractures, spinal cord compression, bladder outlet obstruction, exacerbation of pain) were assessed retrospectively. Such complications were extremely rare (<1%) in both groups. There was no difference whether or not antiandrogens were administered. The timing of antiandrogen prescription(0-6 vs > or =7 d before starting the LHRH analogues) made no difference.The authors concluded that no evidence supports a generalised use of antiandrogens in addition to the LHRH agonists. The risks of antiandrogen therapy (hepatic,gastrointestinal, ocular, and pulmonary complications)may counterbalance the benefits of the combined therapy,which is much more expensive.
- Activity of antiandrogens against juvenile and adult Schistosoma mansoni in mice. [Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't]
- J Antimicrob Chemother 2010 Sep; 65(9):1991-5.
The antischistosomal properties of the marketed antiandrogens bicalutamide, flutamide, nilutamide and cyproterone acetate were studied both in vivo and in vitro.Schistosoma mansoni-infected mice were treated orally with 50-400 mg/kg of the antiandrogens 3 and 7 weeks post-infection. In addition, three drug combinations of nilutamide and praziquantel (200/100, 100/100 and 100/50 mg/kg) were administered to mice harbouring adult S. mansoni. Drug effects were also monitored in vitro following exposure to antiandrogen concentrations of 1, 10 and 100 microg/mL.Low total worm burden reductions (5%-37%) and low to moderate female worm burden reductions (13%-75%) were achieved with the antiandrogens in the S. mansoni juvenile infection model. While flutamide and cyproterone acetate lacked activity against adult S. mansoni in vivo, low to moderate total and female worm burden reductions (0%-47%) were observed with bicalutamide. The highest total and female worm burden reductions (85% and 71%, respectively) (P < 0.001) were documented following a single 400 mg/kg dose of nilutamide. Statistically significant total (91%) and female (85%) worm burden reductions were achieved with the combination of nilutamide (200 mg/kg) and praziquantel (100 mg/kg). Schistosomes incubated with 100 microg/mL cyproterone acetate in vitro died after 15 h. Incubation with bicalutamide, nilutamide and flutamide at 100 microg/mL resulted in decreased movement of S. mansoni adults.Our data indicate that the hydantoin derivative nilutamide has interesting antischistosomal properties, confirming previous results of schistosomicidal activities of this drug class.
- Hormonal therapy of prostate cancer. [Journal Article]
- Prog Brain Res 2010.:321-41.
Of all cancers, prostate cancer is the most sensitive to hormones: it is thus very important to take advantage of this unique property and to always use optimal androgen blockade when hormone therapy is the appropriate treatment. A fundamental observation is that the serum testosterone concentration only reflects the amount of testosterone of testicular origin which is released in the blood from which it reaches all tissues. Recent data show, however, that an approximately equal amount of testosterone is made from dehydroepiandrosterone (DHEA) directly in the peripheral tissues, including the prostate, and does not appear in the blood. Consequently, after castration, the 95-97% fall in serum testosterone does not reflect the 40-50% testosterone (testo) and dihydrotestosterone (DHT) made locally in the prostate from DHEA of adrenal origin. In fact, while elimination of testicular androgens by castration alone has never been shown to prolong life in metastatic prostate cancer, combination of castration (surgical or medical with a gonadotropin-releasing hormone (GnRH) agonist) with a pure anti-androgen has been the first treatment shown to prolong life. Most importantly, when applied at the localized stage, the same combined androgen blockade (CAB) can provide long-term control or cure of the disease in more than 90% of cases. Obviously, since prostate cancer usually grows and metastasizes without signs or symptoms, screening with prostate-specific antigen (PSA) is absolutely needed to diagnose prostate cancer at an 'early' stage before metastasis occurs and the cancer becomes non-curable. While the role of androgens was believed to have become non-significant in cancer progressing under any form of androgen blockade, recent data have shown increased expression of the androgen receptor (AR) in treatment-resistant disease with a benefit of further androgen blockade. Since the available anti-androgens have low affinity for AR and cannot block androgen action completely, especially in the presence of increased AR levels, it becomes important to discover more potent and purely antagonistic blockers of AR. The data obtained with compounds under development are promising. While waiting for this (these) new anti-androgen(s), combined treatment with castration and a pure anti-androgen (bicalutamide, flutamide or nilutamide) is the only available and the best scientifically based means of treating prostate cancer by hormone therapy at any stage of the disease with the optimal chance of success and even cure in localized disease.
- Involvement of androgen receptor in nitric oxide production induced by icariin in human umbilical vein endothelial cells. [Journal Article]
- FEBS Lett 2010 Jun 3; 584(11):2440-4.
Icariin, a flavonoid isolated from Epimedii herba, stimulated phosphorylation of endothelial nitric oxide synthase (eNOS) at Ser1177, Akt (Ser473) and ERK1/2 (Thr202/Tyr204). The icariin-induced eNOS phosphorylation was abolished by an androgen receptor (AR) antagonist, nilutamide in human umbilical vein endothelial cells (HUVECs). Furthermore, it was also reduced in the cells transfected with small interfering RNA in which the expression of AR was broken down. The icariin-induced eNOS phosphorylation was inhibited by wortmannin, a phosphatidylinositol 3-kinase (PI3K) inhibitor and partially attenuated by PD98059, an upstream inhibitor for ERK1/2. These data suggest that icariin stimulates release of NO by AR-dependent activation of eNOS in HUVECs. PI3K/Akt and MAPK-ERK kinase (MEK)/ERK1/2 pathways were involved in the phosphorylation of eNOS by icariin.
- Androgen receptor-dependent activation of endothelial nitric oxide synthase in vascular endothelial cells: role of phosphatidylinositol 3-kinase/akt pathway. [Journal Article, Research Support, Non-U.S. Gov't]
- Endocrinology 2010 Apr; 151(4):1822-8.
The mechanisms of testosterone-induced vasodilatation are not fully understood. This study investigated the effect of testosterone on nitric oxide (NO) synthesis and its molecular mechanism using human aortic endothelial cells (HAEC). Testosterone at physiological concentrations (1-100 nm) induced a rapid (15-30 min) increase in NO production, which was associated with phosphorylation and activation of endothelial NO synthase (eNOS). Then, the involvement of the androgen receptor (AR), which is abundantly expressed in HAEC, was examined. The effect of testosterone on eNOS activation and NO production were abolished by pretreatment with an AR antagonist nilutamide and by transfection with AR small interference RNA. In contrast, testosterone-induced eNOS phosphorylation was unchanged by pretreatment with an aromatase inhibitor or by transfection with ERalpha small interference RNA. 5alpha-Dihydrotestosterone, a nonaromatizable androgen, also stimulated eNOS phosphorylation. Next, the signaling cascade that leads to eNOS phosphorylation was explored. Testosterone stimulated rapid phosphorylation of Akt in a time- and dose-dependent manner, with maximal response at 15-60 min. The rapid phosphorylation of eNOS or NO production induced by testosterone was inhibited by Akt inhibitor SH-5 or by phosphatidylinositol (PI) 3-kinase inhibitor wortmannin. Co-immunoprecipitation assays revealed a testosterone-dependent interaction between AR and the p85alpha subunit of PI3-kinase. In conclusion, testosterone rapidly induces NO production via AR-dependent activation of eNOS in HAEC. Activation of PI3-kinase/Akt signaling and the direct interaction of AR with p85alpha are involved, at least in part, in eNOS phosphorylation.
- Neoadjuvant androgen deprivation for prostate volume reduction: the optimal duration in prostate cancer radiotherapy. [Clinical Trial, Phase II, Journal Article]
- Urol Oncol 2011 Jan-Feb; 29(1):52-7.
For locally advanced prostate cancer, the results of radiotherapy are improved by combination with androgen deprivation therapy. Volume reduction achieved with neoadjuvant hormonal treatment can facilitate dose escalation without increasing the toxicity. The optimal duration of hormonal treatment, however, is unknown. The endpoint of this study is the optimal duration of androgen deprivation for prostate volume reduction in a cohort of patients scheduled for external beam radiotherapy.Twenty patients scheduled for external beam radiotherapy with cT2-3No/xMo prostate cancer were treated with a luteinizing hormone releasing hormone agonist (busereline) and nonsteroidal anti-androgen (nilutamide) for 9 months consecutively. Repeated CT scan examination was performed 3-monthly to measure prostate volumes until the start of radiation therapy. The analysis of volume reduction was performed with the Wilcoxon signed ranks test.The baseline median prostate volume for the cohort of patients was 82 cc (95% CI: 61-104 cc) with a median volume reduction of 31% (95% CI: 26%-35%) (P < 0.0001) after 3 months of androgen deprivation. Between 3 and 6 months, a median volume reduction of 9% (95% CI: 4%-14%) (P < 0.0001) was observed. The effect was more pronounced in large prostates (>60 cc) than in small prostates (≤60 cc). In the total cohort of patients no significant volume reduction occurred between 6 and 9 months of maximal androgen blockade (MAB).In this study, we have shown that the most significant prostate volume reduction is achieved after 3 months of MAB with a maximum reduction after 6 months. Therefore, the optimal duration of neoadjuvant androgen deprivation to reduce prostate volume before prostate cancer radiotherapy is 6 months. In small prostates 3 months of hormonal treatment may be enough for maximal volume reduction.
- Efficacy of salvage radiotherapy plus 2-year androgen suppression for postradical prostatectomy patients with PSA relapse. [Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't]
- Int J Radiat Oncol Biol Phys 2009 Nov 15; 75(4):983-9.
To determine the efficacy of a combined approach of radiotherapy (RT) plus 2-year androgen suppression (AS) as salvage treatment for prostate-specific antigen (PSA) relapse after radical prostatectomy (RP).Seventy-five patients with PSA relapse after RP were treated with salvage RT plus 2-year AS, as per a pilot, prospective study. AS started within 1 month after completion of salvage RT and consisted of nilutamide for 4 weeks and buserelin acetate depot subcutaneously every 2 months for 2 years. Relapse-free rate including freedom from PSA relapse was estimated using the Kaplan-Meier method. PSA relapse was defined as a PSA rise above 0.2 ng/mL with two consecutive increases over a minimum of 3 months. A Cox regression analysis was performed to evaluate prognostic factors for relapse.Median age of the cohort was 63 years at the time of salvage RT. Median follow-up from salvage RT was 6.4 years. All achieved initially complete PSA response (< 0.2) with the protocol treatment. Relapse-free rate including the freedom from PSA relapse was 91.5% at 5 years and 78.6% at 7 years. Overall survival rate was 93.2% at both 5 and 7 years. On Cox regression analysis, pT3 stage and PSA relapse less than 2 years after RP were significant prognostic factors for relapse.The combined treatment of salvage RT plus 2-year AS yielded an encouraging result for patients with PSA relapse after RP and needs a confirmatory study.
- Prospective study evaluating postoperative radiotherapy plus 2-year androgen suppression for post-radical prostatectomy patients with pathologic T3 disease and/or positive surgical margins. [Evaluation Studies, Journal Article, Research Support, Non-U.S. Gov't]
- Int J Radiat Oncol Biol Phys 2009 Oct 1; 75(2):407-12.
To determine the efficacy of a combined approach of postoperative radiotherapy (RT) plus 2-year androgen suppression (AS) for patients with pathologic T3 disease (pT3) and/or positive surgical margins (PSM) after radical prostatectomy (RP).A total of 78 patients with pT3 and/or PSM after RP were treated with RT plus 2-year AS, as per a pilot, prospective study. Androgen suppression started within 1 month after the completion of RT and consisted of nilutamide for 4 weeks and buserelin acetate depot subcutaneously every 2 months for 2 years. Relapse-free rate, including freedom from prostate-specific antigen (PSA) relapse, was estimated using the Kaplan-Meier method. A Cox regression analysis was performed to evaluate prognostic factors for relapse. Prostate-specific antigen relapse was defined as a PSA rise above 0.2 ng/mL, with two consecutive increases over a minimum of 3 months.The median age was 61 years at the time of RP. The median interval between RP and postoperative RT was 4.2 months. Forty-nine patients had undetectable PSA (<0.2 ng/mL), and 29 had persistently detectable postoperative PSA at the time of the protocol treatment. Median follow-up from RT was 6.4 years. Relapse-free rates at 5 and 7 years were 94.4% and 86.3%, respectively. Survival rates were 96% at 5 years and 93.1% at 7 years. On Cox regression analysis, persistently detectable postoperative PSA and pT3b-T4 were significant predictors for relapse.The combined treatment of postoperative RT plus 2-year AS yielded encouraging results for patients with pT3 and/or PSM and warrants a confirmatory study.
- Watchful waiting beats androgen deprivation therapy in early prostate cancer. [News]
- J Natl Cancer Inst 2008 Nov 5; 100(21):1494-6.
- Testosterone recovery after prolonged androgen suppression in patients with prostate cancer. [Clinical Trial, Phase II, Comparative Study, Journal Article, Research Support, Non-U.S. Gov't]
- J Urol 2008 Oct; 180(4):1438-43; discussion 1443-4.
We prospectively examined the extent and timing of testosterone recovery in patients with prostate cancer treated with 2 years of androgen suppression.A total of 153 patients with pT3N0M0 prostate cancer or positive margins after radical prostatectomy, or with prostate specific antigen relapse were treated with radiation to the prostate bed plus 2 years of androgen suppression as per a phase II study. Androgen suppression consisted of nilutamide for 4 weeks plus busereline acetate bimonthly for 2 years. Serum testosterone was measured at baseline, every 4 months during androgen suppression and every 6 months after androgen suppression during followup. Testosterone recovery to supracastrate levels, and to baseline and/or normal levels was estimated using Kaplan-Meier methods. Prognostic factors for testosterone recovery were examined.A total of 121 patients who completed 2 years of androgen suppression and 20 patients who received shorter durations of androgen suppression (median 16 months) were available for testosterone recovery analysis. Median followup after finishing androgen suppression was 38.9 months. All patients achieved castrate levels on androgen suppression. At 36 months after completion of androgen suppression 93.2% and 71.5% had recovery to supracastrate (median time 12.7 months), and to baseline and/or normal testosterone levels (median time 22.3 months), respectively. On multivariate analysis younger age (younger than 60 years, p = 0.0006) and shorter androgen suppression duration (less than 2 years, p = 0.028) were prognostic for faster recovery to baseline and/or normal testosterone levels after adjusting for baseline testosterone levels (p = 0.447).Testosterone recovery after prolonged androgen suppression is protracted. Older age and longer duration of androgen suppression result in significantly longer recovery times to baseline and/or normal testosterone levels.