Kyprianou N, Chon J, Benning C M
Division of Urology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
Prostate Suppl. 2000;9:42-6. doi: 10.1002/1097-0045(2000)45:9+<42::aid-pros9>3.0.co;2-u.
Benign prostate hyperplasia (BPH) and prostate cancer established that disruption of the molecular mechanisms that regulate apoptosis and cell proliferation among the stromal and epithelial cell populations, may underlie the neoplastic development that characterizes the aging gland. This work examined the effects of selected alpha(1)-adrenoceptor (alpha(1)-AR) antagonists (blockers) on cellular dynamics to determine whether induction of apoptosis or inhibition of proliferation could contribute to the overall clinical profile.
Our efforts were focused on investigating whether alpha(1)-AR antagonists of two different chemical classes affect prostate pathophysiology via mechanisms other than smooth muscle contraction. In in vitro experiments, the two clinically used quinazoline alpha(1)-adrenoceptor antagonists terazosin and doxazosin and the chemically-distinct sulphonamide, tamsulosin, were examined for effects on prostatic tumor growth, by inhibiting cell proliferation and'or inducing apoptosis.
Our findings suggest that alpha(1)-AR antagonists, terazosin and doxazosin, suppress prostatic growth by inducing apoptosis in a dose-dependent manner and without affecting cell proliferation. Tamsulosin exerted no effect on prostate cancer cell growth. The apoptotic effect of terazosin and doxazosin appears to be independent of the alpha(1)-adrenoceptor block.
Taken together, our findings demonstrate the ability of the quinazoline alpha-blockers, terazosin and doxazosin, but not the sulphonamide, tamsulosin, to suppress prostate growth by inducing apoptosis among the epithelial cells in the benign and malignant prostate. These studies underwrite the durability of the response seen in long-term studies with terazosin, and suggest the potential of this drug in the treatment of prostate carcinoma.
良性前列腺增生（BPH）和前列腺癌表明，调节基质和上皮细胞群体中细胞凋亡和细胞增殖的分子机制的破坏，可能是衰老腺体特征性肿瘤发展的基础。这项工作研究了选定的α（1）-肾上腺素能受体（α（1）-AR）拮抗剂（阻滞剂）对细胞动力学的影响，以确定细胞凋亡的诱导或增殖的抑制是否有助于整体临床特征。
我们的研究重点是调查两种不同化学类别的α（1）-AR拮抗剂是否通过平滑肌收缩以外的机制影响前列腺病理生理学。在体外实验中，通过抑制细胞增殖和/或诱导细胞凋亡，检测了两种临床使用的喹唑啉α（1）-肾上腺素能受体拮抗剂特拉唑嗪和多沙唑嗪以及化学性质不同的磺酰胺坦索罗辛对前列腺肿瘤生长的影响。
我们的研究结果表明，α（1）-AR拮抗剂特拉唑嗪和多沙唑嗪通过以剂量依赖性方式诱导细胞凋亡来抑制前列腺生长，而不影响细胞增殖。坦索罗辛对前列腺癌细胞生长没有影响。特拉唑嗪和多沙唑嗪的凋亡作用似乎与α（1）-肾上腺素能受体阻滞无关。
综上所述，我们的研究结果表明，喹唑啉α阻滞剂特拉唑嗪和多沙唑嗪能够通过诱导良性和恶性前列腺上皮细胞凋亡来抑制前列腺生长，而磺酰胺坦索罗辛则不能。这些研究证实了特拉唑嗪长期研究中所见反应的持久性，并表明该药物在治疗前列腺癌方面的潜力。
