Kyprianou N, Litvak J P, Borkowski A, Alexander R, Jacobs S C
Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore 21201, USA.
J Urol. 1998 Jun;159(6):1810-5. doi: 10.1016/S0022-5347(01)63162-8.
The molecular mechanisms underlying the therapeutic effect of the alpha1 blocker, doxazosin, on benign prostatic hyperplasia (BPH) are poorly understood. We evaluated the effect of doxazosin on cell proliferation and apoptosis in the prostatic glandular epithelium and stroma of patients with BPH.
We examined proliferative and apoptotic activities in prostate specimens of 22 men a mean of 65 years old with BPH before and after doxazosin treatment within the normal therapeutic range. Proliferative and apoptotic indexes were determined using Ki-67 nuclear antigen staining and the terminal transferase end labeling assay, respectively. The smooth muscle cell content in prostatic specimens was identified by smooth muscle alpha-actin, and desmin immunoreactivity and apoptotic indexes were correlated with prostatic stromal tissue regression and improvement in BPH symptoms.
In response to doxazosin treatment there were no significant changes in the kinetics of cell proliferation in the prostatic epithelial or stromal cell population. Mean pretreatment baseline apoptosis was 1.9 and 1.0% for the epithelial and stromal prostate components, respectively. Mean apoptotic indexes significantly increased after 3 months of doxazosin treatment in the glandular epithelial (6%) and smooth muscle cells (15%). By 12 months after treatment epithelial apoptosis had decreased to constitutive levels, while the apoptotic index of prostatic stroma cells remained high. Doxazosin induced smooth muscle cell apoptosis correlated with prostatic stromal degeneration, decreased alpha-smooth muscle actin expression and improved BPH symptoms.
These findings implicate the induction of prostate apoptosis by doxazosin as a potential molecular mechanism underlying the acute and chronic therapeutic responses of BPH to alpha1 blockade.
α1受体阻滞剂多沙唑嗪对良性前列腺增生（BPH）的治疗作用背后的分子机制尚不清楚。我们评估了多沙唑嗪对BPH患者前列腺腺上皮和基质中细胞增殖和凋亡的影响。
我们检查了22名平均年龄65岁的BPH男性患者在正常治疗范围内接受多沙唑嗪治疗前后前列腺标本中的增殖和凋亡活性。分别使用Ki-67核抗原染色和末端转移酶末端标记法测定增殖指数和凋亡指数。通过平滑肌α-肌动蛋白鉴定前列腺标本中的平滑肌细胞含量，结蛋白免疫反应性和凋亡指数与前列腺基质组织消退及BPH症状改善相关。
多沙唑嗪治疗后，前列腺上皮或基质细胞群体的细胞增殖动力学无显著变化。上皮和基质前列腺成分的平均预处理基线凋亡率分别为1.9%和1.0%。多沙唑嗪治疗3个月后，腺上皮（6%）和平滑肌细胞（15%）的平均凋亡指数显著增加。治疗12个月后，上皮凋亡降至基础水平，而前列腺基质细胞的凋亡指数仍较高。多沙唑嗪诱导的平滑肌细胞凋亡与前列腺基质变性、α-平滑肌肌动蛋白表达降低及BPH症状改善相关。
这些发现表明多沙唑嗪诱导前列腺凋亡是BPH对α1受体阻滞急性和慢性治疗反应潜在的分子机制。
