α1-adrenoceptor antagonists terazosin and doxazosin induce prostate apoptosis without affecting cell proliferation in patients with benign prostatic hyperplasia

被引:122
作者
Chon, JK
Borkowski, A
Partin, AW
Isaacs, JT
Jacobs, SC
Kyprianou, N
机构
[1] Univ Maryland, Sch Med, Div Urol, Baltimore, MD 21201 USA
[2] Univ Maryland, Sch Med, Dept Surg, Baltimore, MD 21201 USA
[3] Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA
[4] Univ Maryland, Sch Med, Dept Biochem & Mol Biol, Baltimore, MD 21201 USA
[5] Johns Hopkins Univ, Sch Med, James Buchanan Brady Urol Inst, Baltimore, MD USA
[6] Johns Hopkins Univ, Sch Med, Ctr Oncol, Baltimore, MD USA
关键词
alpha-adrenaceptor antagonists; cell proliferation; apoptosis; prostate; doxazosin; terazosin;
D O I
10.1016/S0022-5347(05)68873-8
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
Purpose: Recent evidence indicated that an alpha(1) blocker, doxazosin, induces prostate apoptosis in patients with benign prostatic hyperplasia (BPH).(1) In this study, to determine whether this apoptotic response was mediated by alpha(1) adrenoceptor-dependent mechanism or was specific to doxazosin, we examined the effect of another alpha(1) blocker, terazosin, in addition to doxazosin, on the dynamics of prostate cell growth. Materials and Methods: Cell proliferation and apoptosis were evaluated in BPH patients, an untreated (control) group (n = 31), and men treated with terazosin (n = 42) and doxazosin (n = 61) for the relief of the obstructive symptoms. Terazosin (1 to 10 mg./day) and doxazosin (2 to 8 mg./day) treatment varied from 1 week to 3 years. Ki-67 immunostaining and the TUNEL assay were used to evaluate the proliferative and apoptotic indices, respectively, in both the epithelial and stromal components of prostate (biopsy and prostatectomy) specimens. The smooth muscle cell content of the prostatic stroma was identified on the basis of smooth muscle alpha-actin immunoreactivity. Results: A significant induction of apoptosis was observed in both the prostatic epithelial and stromal cells within the first month of terazosin and doxazosin therapy, as compared with untreated controls (p<0.05). Furthermore, the marked induction of prostatic stroma apoptosis in response to both alpha(1) adrenoceptor antagonists was paralleled by a significant decrease in the smooth muscle alpha-actin expression. This loss of prostatic smooth muscle cells correlated with morphological stromal regression las detected by trichrome staining) and BPH symptom improvement. Neither terazosin nor doxazosin therapy resulted in significant changes in prostate cell proliferation. Conclusions: These findings demonstrate that alpha-blockers as a class may regulate prostate growth by inducing apoptosis in both the epithelial and stromal cells, with little effect on cell proliferation. Apoptosis-mediated prostate stromal regression appears as a molecular mechanism underlying the therapeutic response to alpha(1) blockade in the treatment of BPH.
引用
收藏
页码:2002 / 2008
页数:7
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