alpha(1)-adrenoceptor antagonists terazosin and doxazosin induce prostate apoptosis without affecting cell proliferation in patients with benign prostatic hyperplasia
Jk. Chon et al., alpha(1)-adrenoceptor antagonists terazosin and doxazosin induce prostate apoptosis without affecting cell proliferation in patients with benign prostatic hyperplasia, J UROL, 161(6), 1999, pp. 2002-2008
Purpose: Recent evidence indicated that an alpha(1) blocker, doxazosin, ind
uces prostate apoptosis in patients with benign prostatic hyperplasia (BPH)
.(1) In this study, to determine whether this apoptotic response was mediat
ed by alpha(1) adrenoceptor-dependent mechanism or was specific to doxazosi
n, we examined the effect of another alpha(1) blocker, terazosin, in additi
on to doxazosin, on the dynamics of prostate cell growth.
Materials and Methods: Cell proliferation and apoptosis were evaluated in B
PH patients, an untreated (control) group (n = 31), and men treated with te
razosin (n = 42) and doxazosin (n = 61) for the relief of the obstructive s
ymptoms. Terazosin (1 to 10 mg./day) and doxazosin (2 to 8 mg./day) treatme
nt 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 pro
statectomy) specimens. The smooth muscle cell content of the prostatic stro
ma was identified on the basis of smooth muscle alpha-actin immunoreactivit
y.
Results: A significant induction of apoptosis was observed in both the pros
tatic epithelial and stromal cells within the first month of terazosin and
doxazosin therapy, as compared with untreated controls (p<0.05). Furthermor
e, the marked induction of prostatic stroma apoptosis in response to both a
lpha(1) adrenoceptor antagonists was paralleled by a significant decrease i
n the smooth muscle alpha-actin expression. This loss of prostatic smooth m
uscle cells correlated with morphological stromal regression las detected b
y trichrome staining) and BPH symptom improvement. Neither terazosin nor do
xazosin therapy resulted in significant changes in prostate cell proliferat
ion.
Conclusions: These findings demonstrate that alpha-blockers as a class may
regulate prostate growth by inducing apoptosis in both the epithelial and s
tromal 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.