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Natasha Kyprianou - One of the best experts on this subject based on the ideXlab platform.

  • Doxazosin induces apoptosis of benign and malignant prostate cells via a death receptor mediated pathway
    Cancer Research, 2006
    Co-Authors: Jason B Garrison, Natasha Kyprianou
    Abstract:

    Quinazoline-based α1-adrenoceptor antagonists such as Doxazosin and terazosin have been previously shown to induce apoptosis in prostate cancer cells via an α1-adrenoceptor–independent pathway, involving activation of transforming growth factor-β1 (TGF-β1) signaling. In this study, the molecular events initiating this apoptotic effect were further investigated in vitro using the human androgen-independent prostate cancer cells PC-3 and the human benign prostate epithelial cells BPH-1. Quantitative microarray assays were done in PC-3 and BPH-1 cells after treatment with Doxazosin (25 μmol/L, 6 and 24 hours) to identify the early gene changes. Transient changes in the expression of several apoptosis regulators were identified, including up-regulation of Bax and Fas/CD95 and down-regulation of Bcl-xL and TRAMP/Apo3. Moreover, there were significant changes in the expression pattern of signaling components of the extracellular matrix such as integrins α2, αV, β1, and β8. Western blot analysis revealed activation of caspase-8 and caspase-3 within the first 6 to 12 hours of treatment with Doxazosin in both PC-3 and BPH-1 cells. Doxazosin-induced apoptosis was blocked by specific caspase-8 inhibitors, supporting the functional involvement of caspase-8 in Doxazosin-induced apoptosis. The effect of Doxazosin on recruitment of Fas-associated death domain (FADD) and procaspase-8 to the Fas receptor was examined via analysis of death-inducing signaling complex formation. Doxazosin increased FADD recruitment and subsequent caspase-8 activation, implicating Fas-mediated apoptosis as the underlying mechanism of the effect of Doxazosin in prostate cells. These results show that Doxazosin exerts its apoptotic effects against benign and malignant prostate cells via a death receptor–mediated mechanism with a potential integrin contribution towards cell survival outcomes. (Cancer Res 2006; 66(1): 464-72)

  • maspin sensitizes prostate cancer cells to Doxazosin induced apoptosis
    Oncogene, 2005
    Co-Authors: Anastasios Tahmatzopoulos, Shijie Sheng, Natasha Kyprianou
    Abstract:

    : Maspin is a mammary serine protease inhibitor or serpin with tumor suppressive and antiangiogenic activity that inhibits tumor motility, invasion and metastasis, at least by its actions on cell membrane and extracellular matrix (ECM) proteins. Previous studies documented that the quinazoline-derived alpha1-adrenoceptor antagonist Doxazosin affects the attachment and migration of prostate cancer cells. In this study, we investigated the effect of maspin overexpression on the apoptotic/antiadhesion response of prostate cancer cells to Doxazosin. The response of maspin-overexpressing clones of human prostate cancer cells DU-145 to Doxazosin was evaluated by determining cell viability, apoptosis and cell proliferation on the basis of the trypan blue exclusion assay/methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay, Hoechst staining and caspase-3 activation, and [(3)H]thymidine incorporation assay. Vascular endothelial growth factor (VEGF), transforming growth factor betaRII (TGFbetaRII), Smad4 (a TGFbeta intracellular effector) and bax expression was evaluated at the mRNA and protein level using reverse transcriptase-polymerase chain reaction and Western blotting, respectively. The effect of Doxazosin on cell attachment of maspin-expressing prostate cancer cells was evaluated on collagen- and fibronectin-coated plates. Cell migration was assessed using the wounding assay. In response to tumor necrosis factor-related apoptosis-inducing ligand, DU-145-maspin expressing cells undergo apoptosis, via poly(ADP-ribose) polymerasecleavage and caspase-3 activation. DU-145-maspin cells exhibited higher sensitivity to Doxazosin and an earlier temporal activation of caspase-3. The number of apoptotic cells detected in response to Doxazosin was significantly higher compared to the neo control (P<0.0001). Doxazosin resulted in dramatic downregulation of the 189 isoform of VEGF in maspin transfectants, while a fivefold induction of Smad4 mRNA expression was detected in those cells after 24 h of treatment. Maspin overexpression in prostate cancer cells resulted in an increased ability to attach to ECM-coated plates, and Doxazosin treatment considerably antagonized this effect by decreasing the attachment potential to collagen and fibronectin. The present study supports the ability of maspin to enhance the apoptotic threshold of prostate cancer cells to the quinazoline-based alpha1-adrenoceptor antagonist Doxazosin. These findings may have therapeutic significance in the development of antiangiogenic targeting by Doxazosin and derivative agents for advanced prostate cancer.

  • Doxazosin inhibits human vascular endothelial cell adhesion, migration, and invasion
    Journal of Cellular Biochemistry, 2005
    Co-Authors: Kaspar Keledjian, Jason B Garrison, Natasha Kyprianou
    Abstract:

    The quinazoline-derived α1-adrenoceptor antagonists, Doxazosin and terazosin have been recently shown to induce an anoikis effect in human prostate cancer cells and to suppress prostate tumor vascularity in clinical specimens [Keledjian and Kyprianou, 2003]. This study sought to examine the ability of Doxazosin to affect the growth of human vascular endothelial cells and to modulate vascular endothelial growth factor (VEGF)-mediated angiogenesis. Human umbilical vein endothelial cells (HUVECs) were used as an in vitro model to determine the effect of Doxazosin on cell growth, apoptosis, adhesion, migration, and angiogenic response of endothelial cells. The effect of Doxazosin on cell viability and apoptosis induction of human endothelial cells, was evaluated on the basis of trypan blue and Hoechst 33342 staining, respectively. Doxazosin antagonized the VEGF-mediated angiogenic response of HUVEC cells, by abrogating cell adhesion to fibronectin and collagen-coated surfaces and inhibiting cell migration, via a potential downregulation of VEGF expression. Furthermore there was a significant suppression of in vitro angiogenesis by Doxazosin on the basis of VEGF-mediated endothelial tube formation (P 

  • Doxazosin inhibits human vascular endothelial cell adhesion migration and invasion
    Journal of Cellular Biochemistry, 2005
    Co-Authors: Kaspar Keledjian, Jason B Garrison, Natasha Kyprianou
    Abstract:

    The quinazoline-derived α1-adrenoceptor antagonists, Doxazosin and terazosin have been recently shown to induce an anoikis effect in human prostate cancer cells and to suppress prostate tumor vascularity in clinical specimens [Keledjian and Kyprianou, 2003]. This study sought to examine the ability of Doxazosin to affect the growth of human vascular endothelial cells and to modulate vascular endothelial growth factor (VEGF)-mediated angiogenesis. Human umbilical vein endothelial cells (HUVECs) were used as an in vitro model to determine the effect of Doxazosin on cell growth, apoptosis, adhesion, migration, and angiogenic response of endothelial cells. The effect of Doxazosin on cell viability and apoptosis induction of human endothelial cells, was evaluated on the basis of trypan blue and Hoechst 33342 staining, respectively. Doxazosin antagonized the VEGF-mediated angiogenic response of HUVEC cells, by abrogating cell adhesion to fibronectin and collagen-coated surfaces and inhibiting cell migration, via a potential downregulation of VEGF expression. Furthermore there was a significant suppression of in vitro angiogenesis by Doxazosin on the basis of VEGF-mediated endothelial tube formation (P < 0.01). Fibroblast growth factor-2 (FGF-2) significantly enhanced HUVEC cell tube formation (P < 0.01) and this effect was suppressed by Doxazosin. These findings provide new insight into the ability of Doxazosin to suppress the growth and angiogenic response of human endothelial cells by interfering with VEGF and FGF-2 action. This evidence may have potential therapeutic significance in using this quinazoline-based compound as an antiangiogenic agent for the treatment of advanced prostate cancer. © 2004 Wiley-Liss, Inc.

Jason B Garrison - One of the best experts on this subject based on the ideXlab platform.

  • Doxazosin induces apoptosis of benign and malignant prostate cells via a death receptor mediated pathway
    Cancer Research, 2006
    Co-Authors: Jason B Garrison, Natasha Kyprianou
    Abstract:

    Quinazoline-based α1-adrenoceptor antagonists such as Doxazosin and terazosin have been previously shown to induce apoptosis in prostate cancer cells via an α1-adrenoceptor–independent pathway, involving activation of transforming growth factor-β1 (TGF-β1) signaling. In this study, the molecular events initiating this apoptotic effect were further investigated in vitro using the human androgen-independent prostate cancer cells PC-3 and the human benign prostate epithelial cells BPH-1. Quantitative microarray assays were done in PC-3 and BPH-1 cells after treatment with Doxazosin (25 μmol/L, 6 and 24 hours) to identify the early gene changes. Transient changes in the expression of several apoptosis regulators were identified, including up-regulation of Bax and Fas/CD95 and down-regulation of Bcl-xL and TRAMP/Apo3. Moreover, there were significant changes in the expression pattern of signaling components of the extracellular matrix such as integrins α2, αV, β1, and β8. Western blot analysis revealed activation of caspase-8 and caspase-3 within the first 6 to 12 hours of treatment with Doxazosin in both PC-3 and BPH-1 cells. Doxazosin-induced apoptosis was blocked by specific caspase-8 inhibitors, supporting the functional involvement of caspase-8 in Doxazosin-induced apoptosis. The effect of Doxazosin on recruitment of Fas-associated death domain (FADD) and procaspase-8 to the Fas receptor was examined via analysis of death-inducing signaling complex formation. Doxazosin increased FADD recruitment and subsequent caspase-8 activation, implicating Fas-mediated apoptosis as the underlying mechanism of the effect of Doxazosin in prostate cells. These results show that Doxazosin exerts its apoptotic effects against benign and malignant prostate cells via a death receptor–mediated mechanism with a potential integrin contribution towards cell survival outcomes. (Cancer Res 2006; 66(1): 464-72)

  • Doxazosin inhibits human vascular endothelial cell adhesion, migration, and invasion
    Journal of Cellular Biochemistry, 2005
    Co-Authors: Kaspar Keledjian, Jason B Garrison, Natasha Kyprianou
    Abstract:

    The quinazoline-derived α1-adrenoceptor antagonists, Doxazosin and terazosin have been recently shown to induce an anoikis effect in human prostate cancer cells and to suppress prostate tumor vascularity in clinical specimens [Keledjian and Kyprianou, 2003]. This study sought to examine the ability of Doxazosin to affect the growth of human vascular endothelial cells and to modulate vascular endothelial growth factor (VEGF)-mediated angiogenesis. Human umbilical vein endothelial cells (HUVECs) were used as an in vitro model to determine the effect of Doxazosin on cell growth, apoptosis, adhesion, migration, and angiogenic response of endothelial cells. The effect of Doxazosin on cell viability and apoptosis induction of human endothelial cells, was evaluated on the basis of trypan blue and Hoechst 33342 staining, respectively. Doxazosin antagonized the VEGF-mediated angiogenic response of HUVEC cells, by abrogating cell adhesion to fibronectin and collagen-coated surfaces and inhibiting cell migration, via a potential downregulation of VEGF expression. Furthermore there was a significant suppression of in vitro angiogenesis by Doxazosin on the basis of VEGF-mediated endothelial tube formation (P 

  • Doxazosin inhibits human vascular endothelial cell adhesion migration and invasion
    Journal of Cellular Biochemistry, 2005
    Co-Authors: Kaspar Keledjian, Jason B Garrison, Natasha Kyprianou
    Abstract:

    The quinazoline-derived α1-adrenoceptor antagonists, Doxazosin and terazosin have been recently shown to induce an anoikis effect in human prostate cancer cells and to suppress prostate tumor vascularity in clinical specimens [Keledjian and Kyprianou, 2003]. This study sought to examine the ability of Doxazosin to affect the growth of human vascular endothelial cells and to modulate vascular endothelial growth factor (VEGF)-mediated angiogenesis. Human umbilical vein endothelial cells (HUVECs) were used as an in vitro model to determine the effect of Doxazosin on cell growth, apoptosis, adhesion, migration, and angiogenic response of endothelial cells. The effect of Doxazosin on cell viability and apoptosis induction of human endothelial cells, was evaluated on the basis of trypan blue and Hoechst 33342 staining, respectively. Doxazosin antagonized the VEGF-mediated angiogenic response of HUVEC cells, by abrogating cell adhesion to fibronectin and collagen-coated surfaces and inhibiting cell migration, via a potential downregulation of VEGF expression. Furthermore there was a significant suppression of in vitro angiogenesis by Doxazosin on the basis of VEGF-mediated endothelial tube formation (P < 0.01). Fibroblast growth factor-2 (FGF-2) significantly enhanced HUVEC cell tube formation (P < 0.01) and this effect was suppressed by Doxazosin. These findings provide new insight into the ability of Doxazosin to suppress the growth and angiogenic response of human endothelial cells by interfering with VEGF and FGF-2 action. This evidence may have potential therapeutic significance in using this quinazoline-based compound as an antiangiogenic agent for the treatment of advanced prostate cancer. © 2004 Wiley-Liss, Inc.

R S Kirby - One of the best experts on this subject based on the ideXlab platform.

  • efficacy of extended release Doxazosin and Doxazosin standard in patients with concomitant benign prostatic hyperplasia and sexual dysfunction
    BJUI, 2005
    Co-Authors: R S Kirby, Michael P Oleary, Culley C Carson
    Abstract:

    Associate Editor Michael G. Wyllie Editorial Board Ian Eardley, UK Jean Fourcroy, USA Sidney Glina, Brazil Julia Heiman, USA Chris McMahon, Australia Bob Millar, UK Alvaro Morales, Canada Michael Perelman, USA Marcel Waldinger, Netherlands OBJECTIVE To report a comprehensive retrospective analysis of the favourable effects of Doxazosin extended-release (XL) and Doxazosin standard on the sexual health of patients with comorbid benign prostatic hyperplasia (BPH) and erectile dysfunction (ED), augmenting a previous study of 680 patients with symptomatic BPH. PATIENTS AND METHODS Men with BPH and aged 50–80 years participated in a randomized, double- blind, double-dummy, parallel-group, multicentre trial, completing a 2-week, single-blind, placebo run-in period before receiving Doxazosin XL 4 or 8 mg once daily or Doxazosin standard 1–8 mg once daily for 13 weeks. Baseline sexual function and changes from baseline after treatment with Doxazosin were evaluated from responses of the International Index of Erectile Function (IIEF) questionnaire (with dysfunction defined as a score of ≤ 3 for any question) and the five domains for erectile function (intercourse satisfaction, orgasmic function, sexual desire and overall sexual satisfaction). RESULTS Of 680 patients randomized into the trial, 237 (35%) had ED at baseline; in these patients there were statistically and clinically significant improvements in each of the five IIEF domains with XL and standard Doxazosin (P ≤ 0.0019), with the range of improvement being from 13% to 41%. There were no significant differences between treatment groups. Doxazosin XL consistently improved sexual function, as assessed by the individual questions of the IIEF questionnaire. There was no statistically significant difference between groups for any sexual function question analysed. CONCLUSION Doxazosin XL and standard improved sexual function in men with concomitant BPH and ED at baseline. This may represent an action independent of relieving lower urinary tract symptoms, because the beneficial effect of Doxazosin was reported in patients with no symptomatic BPH.

  • efficacy and tolerability of Doxazosin and finasteride alone or in combination in treatment of symptomatic benign prostatic hyperplasia the prospective european Doxazosin and combination therapy predict trial
    Urology, 2003
    Co-Authors: R S Kirby, Claus G Roehrborn, Peter Boyle, Georg Bartsch, Alain Jardin, Margaret M Cary, Michael O Sweeney, Eric Ben Grossman
    Abstract:

    Objectives To evaluate the efficacy and tolerability of the selective alpha1-adrenergic antagonist Doxazosin and the 5-alpha-reductase inhibitor finasteride, alone and in combination, for the symptomatic treatment of benign prostatic hyperplasia. Methods In a prospective, double-blind, placebo-controlled trial, 1095 men aged 50 to 80 years were randomized to treatment for 52 weeks with Doxazosin, finasteride, the combination of Doxazosin and finasteride, or placebo. The dose of finasteride (or its matched placebo) was 5 mg/day. Doxazosin (or its matched placebo) was initiated at 1 mg/day, and titrated up to a maximum of 8 mg/day over approximately 10 weeks according to the response of the maximal urinary flow rate (Qmax) and International Prostate Symptom Score (IPSS). The IPSS and Qmax were assessed at baseline and at weeks 10, 14, 26, 39, and 52 or at the endpoint. Results An intent-to-treat analysis of 1007 men showed Doxazosin and Doxazosin plus finasteride combination therapy produced statistically significant improvements in total IPSS and Qmax compared with placebo and finasteride alone (P <0.05). Finasteride alone was not significantly different statistically from placebo with respect to total IPSS and Qmax. All treatments were generally well tolerated. Conclusions Doxazosin was effective in improving urinary symptoms and urinary flow rate in men with benign prostatic hyperplasia, and was more effective than finasteride alone or placebo. The addition of finasteride did not provide further benefit to that achieved with Doxazosin alone.

  • a randomized double blind crossover study of tamsulosin and controlled release Doxazosin in patients with benign prostatic hyperplasia
    BJUI, 2003
    Co-Authors: R S Kirby
    Abstract:

    OBJECTIVE To compare the effects of the Doxazosin gastrointestinal therapeutic system, extended-release (Doxazosin-GITS) formulation, and tamsulosin, another α1-antagonist, on total International Prostate Symptom Score (IPSS) and maximum urinary flow rate (Qmax) in treating patients with benign prostatic hyperplasia (BPH). PATIENTS AND METHODS Data were analysed from a prospective, randomized, double-blind, crossover study of men aged 50–80 years with concomitant BPH and hypertension as inclusion criteria. Fifty-two men were treated in four phases: phase I, placebo run-in for 2 weeks; phase II, first study drug Doxazosin-GITS or tamsulosin for 8 weeks; phase III, washout with placebo for 2 weeks; and phase IV, second study drug tamsulosin or Doxazosin-GITS for 8 weeks. Doxazosin-GITS was started at 4 mg/day and tamsulosin at 0.4 mg/day, and then titrated to 8 mg/day and 0.8 mg/day, respectively, after 4 weeks of therapy if the increase in Qmax was < 3 mL/s or the reduction in total IPSS was < 30%. Efficacy assessments included the IPSS and Qmax. Changes in blood pressure were not analysed, as most patients were actually not hypertensive. Endpoint efficacy data were analysed using an analysis of covariance model, with terms for sequence, phase, patients and sequence within patients, in addition to the baseline as covariate. Forty-seven men were treated in both efficacy arms of the study and were evaluable for analysis. RESULTS Doxazosin-GITS and tamsulosin significantly relieved lower urinary tract symptoms and significantly increased Qmax from baseline (P = 0.001). Doxazosin-GITS produced significantly greater improvements than tamsulosin in total IPSS (P = 0.019) and obstructive subscores (P = 0.004) at the last treatment visit. The difference between Doxazosin-GITS and tamsulosin in improving Qmax approached significance in favour of the former (mean change from baseline 2.6 vs 1.7 mL/s, respectively; between-group difference P = 0.089). Both treatments were well tolerated. CONCLUSIONS Treatment with Doxazosin-GITS was significantly more effective than tamsulosin in relieving lower urinary tract symptoms.

  • a combined analysis of double blind trials of the efficacy and tolerability of Doxazosin gastrointestinal therapeutic system Doxazosin standard and placebo in patients with benign prostatic hyperplasia
    BJUI, 2001
    Co-Authors: R S Kirby, Morten Andersen, P Gratzke, Christer Dahlstrand, Kjetil Hoye
    Abstract:

    Objective To report an integrated analysis of two previous studies fully characterizing the clinical utility of the controlled-release gastrointestinal therapeutic system (GITS) formulation of Doxazosin in the treatment of benign prostatic hyperplasia (BPH). Patients and methods Two pivotal randomized, double-blind studies of Doxazosin GITS for BPH were assessed by an integrated analysis. Both studies included a 2-week washout period, a 2-week single-blind placebo run-in phase, and a 13-week double-blind treatment phase. One study compared Doxazosin GITS, Doxazosin standard (-S) and placebo in 795 men; the other compared Doxazosin GITS and Doxazosin-S in 680 men. Doxazosin GITS was initiated at 4 mg once daily and titrated to 8 mg once daily after 7 weeks, and Doxazosin-S was initiated at 1 mg once daily and titrated to a maximum of 8 mg once daily over 7 weeks as needed to achieve optimal symptom control. The primary outcome measures were mean changes from baseline to the final visit for the International Prostate Symptom Score (IPSS) and maximum urinary flow rate (Qmax) in the per-protocol population. Numerous symptom- and urinary-related secondary outcomes were assessed, as were effects of therapy on male erectile dysfunction measured using the International Index of Erectile Function (IIEF) in one study. Results Both Doxazosin GITS and Doxazosin-S significantly improved the symptoms of BPH, as shown by a 45% reduction for each in total IPSS from baseline to final visit, compared with a 34% reduction in patients on placebo. Doxazosin GITS and Doxazosin-S produced comparable improvements in Qmax that were significantly greater than with placebo, with a greater improvement sooner after treatment with Doxazosin GITS than with Doxazosin-S. Nearly half of the patients on Doxazosin GITS had symptom relief at the 4-mg starting dose. A similar number of patients in both Doxazosin groups were titrated to the maximum dose. Secondary outcomes were consistent with the primary effects. Both Doxazosin GITS and Doxazosin-S produced significant improvements in sexual function according to IIEF scores among those with dysfunction at baseline. The overall incidence of adverse events was similar among patients treated with Doxazosin GITS and placebo, and slightly lower than those on Doxazosin-S. There was no apparent difference in the type of adverse events reported for the two formulations of Doxazosin, although most adverse events were reported at a lower frequency with Doxazosin GITS. Conclusion Doxazosin GITS is significantly more effective than placebo in reducing the clinical symptoms of BPH and improving Qmax, and as effective as Doxazosin-S. Both Doxazosin formulations improved sexual function in patients with BPH and sexual dysfunction at baseline. Doxazosin GITS produced a therapeutic effect equivalent to that of Doxazosin-S, but with fewer titration steps and a slightly lower overall incidence of adverse events.

  • Morning vs evening dosing with Doxazosin in benign prostatic hyperplasia: efficacy and safety.
    Prostate Cancer and Prostatic Diseases, 1998
    Co-Authors: R S Kirby, Christopher R Chapple, E J G Milroy, K Sethia, M. Flannigan, Paul Abrams
    Abstract:

    Three hundred and fifty-three patients with symptomatic benign prostatic hyperplasia were randomized to Doxazosin or placebo, with morning or evening dosing, to compare the effect of dosing time on the efficacy and safety of Doxazosin treatment. After 24 weeks of treatment, the mean International Prostate Symptom Score had decreased by 6.8 units in the Doxazosin group compared with 4.5 units in the placebo group (P=0.003). Improvements in Qmax of 2.03 ml/s and 0.30 ml/s were seen for the Doxazosin and the placebo groups, respectively (P

Norma Dias - One of the best experts on this subject based on the ideXlab platform.

  • Doxazosin for benign prostatic hyperplasia long term efficacy and safety in hypertensive and normotensive patients
    The Journal of Urology, 1997
    Co-Authors: Herbert Lepor, Michael Gaffney, Ahmed Fawzy, Steven A Kaplan, Ira W Klimberg, David F Mobley, Norma Dias
    Abstract:

    ABSTRACTPurpose: We evaluated the sustained efficacy and safety of Doxazosin for long-term treatment (up to 48 months) of normotensive and hypertensive patients with benign prostatic hyperplasia (BPH).Materials and Methods: A total of 272 normotensive and 178 mildly to moderately hypertensive men entered a long-term extension study of Doxazosin therapy (1 to 8 a to 12 mg. 1 time daily, respectively) for BPH following participation in double-blind, placebo controlled studies. The starting dose of Doxazosin was 1 mg. with upward titrations at 2-week intervals to a stable, efficacious and well tolerated dose. At the time of data analysis patients had received between 1 and 48 months of stable dose Doxazosin therapy (mean 668 days for normotensive and 807 for hypertensive patients). Mean daily doses were 4 and 6.4 mg. for normotensive and hypertensive men, respectively.Results: At the end point analysis Doxazosin treatment resulted in significant increases above baseline in maximum and average urinary flow ra...

  • Doxazosin for the treatment of benign prostatic hyperplasia in patients with mild to moderate essential hypertension a double blind placebo controlled dose response multicenter study
    The Journal of Urology, 1995
    Co-Authors: Jay Y Gillenwater, Richard L Conn, Steven G Chrysant, Michael Gaffney, Norma Dias
    Abstract:

    AbstractA total of 248 hypertensive patients 45 years old or older with benign prostatic hyperplasia (BPH) was included in this 16-week, multicenter, double-blind, placebo-controlled, parallel-group dose-response study. Doxazosin, a selective alpha 1-adrenoceptor antagonist, produced a significant increase in maximum urinary flow rate (2.3 to 3.6 ml. per second) at doses of 4 mg., 8 mg. and 12 mg., and in average flow rate (8 mg. and 12 mg.) compared with placebo. The increase in maximum flow rate was significant with Doxazosin versus placebo within week of initiating double-blind therapy. Doxazosin compared to placebo significantly decreased patient-assessed total, obstructive and irritative BPH symptoms. Blood pressure was significantly lower with all Doxazosin doses compared with placebo. Adverse events, primarily mild to moderate in severity, were reported in 48 percent of patients on Doxazosin and 35 percent on placebo. Our results strongly support the use of Doxazosin as a nonoperative therapeutic a...

Kaspar Keledjian - One of the best experts on this subject based on the ideXlab platform.

  • Doxazosin inhibits human vascular endothelial cell adhesion, migration, and invasion
    Journal of Cellular Biochemistry, 2005
    Co-Authors: Kaspar Keledjian, Jason B Garrison, Natasha Kyprianou
    Abstract:

    The quinazoline-derived α1-adrenoceptor antagonists, Doxazosin and terazosin have been recently shown to induce an anoikis effect in human prostate cancer cells and to suppress prostate tumor vascularity in clinical specimens [Keledjian and Kyprianou, 2003]. This study sought to examine the ability of Doxazosin to affect the growth of human vascular endothelial cells and to modulate vascular endothelial growth factor (VEGF)-mediated angiogenesis. Human umbilical vein endothelial cells (HUVECs) were used as an in vitro model to determine the effect of Doxazosin on cell growth, apoptosis, adhesion, migration, and angiogenic response of endothelial cells. The effect of Doxazosin on cell viability and apoptosis induction of human endothelial cells, was evaluated on the basis of trypan blue and Hoechst 33342 staining, respectively. Doxazosin antagonized the VEGF-mediated angiogenic response of HUVEC cells, by abrogating cell adhesion to fibronectin and collagen-coated surfaces and inhibiting cell migration, via a potential downregulation of VEGF expression. Furthermore there was a significant suppression of in vitro angiogenesis by Doxazosin on the basis of VEGF-mediated endothelial tube formation (P 

  • Doxazosin inhibits human vascular endothelial cell adhesion migration and invasion
    Journal of Cellular Biochemistry, 2005
    Co-Authors: Kaspar Keledjian, Jason B Garrison, Natasha Kyprianou
    Abstract:

    The quinazoline-derived α1-adrenoceptor antagonists, Doxazosin and terazosin have been recently shown to induce an anoikis effect in human prostate cancer cells and to suppress prostate tumor vascularity in clinical specimens [Keledjian and Kyprianou, 2003]. This study sought to examine the ability of Doxazosin to affect the growth of human vascular endothelial cells and to modulate vascular endothelial growth factor (VEGF)-mediated angiogenesis. Human umbilical vein endothelial cells (HUVECs) were used as an in vitro model to determine the effect of Doxazosin on cell growth, apoptosis, adhesion, migration, and angiogenic response of endothelial cells. The effect of Doxazosin on cell viability and apoptosis induction of human endothelial cells, was evaluated on the basis of trypan blue and Hoechst 33342 staining, respectively. Doxazosin antagonized the VEGF-mediated angiogenic response of HUVEC cells, by abrogating cell adhesion to fibronectin and collagen-coated surfaces and inhibiting cell migration, via a potential downregulation of VEGF expression. Furthermore there was a significant suppression of in vitro angiogenesis by Doxazosin on the basis of VEGF-mediated endothelial tube formation (P < 0.01). Fibroblast growth factor-2 (FGF-2) significantly enhanced HUVEC cell tube formation (P < 0.01) and this effect was suppressed by Doxazosin. These findings provide new insight into the ability of Doxazosin to suppress the growth and angiogenic response of human endothelial cells by interfering with VEGF and FGF-2 action. This evidence may have potential therapeutic significance in using this quinazoline-based compound as an antiangiogenic agent for the treatment of advanced prostate cancer. © 2004 Wiley-Liss, Inc.