Pan Shiow-Lin, Guh Jih-Hwa, Huang Ying-Wen, Chern Ji-Wang, Chou Jui-Yi, Teng Che-Ming
Pharmacological Institutes, School of Pharmacy and Department of Urology, College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China.
J Urol. 2003 Feb;169(2):724-9. doi: 10.1097/01.ju.0000037731.83941.db.
It has been suggested that terazosin has an inhibitory effect on prostate tumor growth. We determined if terazosin action contributes to direct suppression of the angiogenic effect.
PC-3 cells and primary cultures of human benign prostatic cells were used in this study. The cytotoxic effect was examined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and lactate dehydrogenase release reaction. The in vivo angiogenic effect was determined in nude mice models, followed by histological examination and quantification by the hemoglobin detection assay. In vitro determination of cell migration, proliferation and tube formation was performed in cultured human umbilical vein endothelial cells. RESULTS Terazosin induced cytotoxicity in PC-3 and human benign prostatic cells with an IC50 of more than 100 microM. The positive terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling and lactate dehydrogenase release reaction was associated with terazosin induced cytotoxicity, indicating apoptotic and necrotic cell death. Furthermore, cytotoxicity due to terazosin action was not a common characteristic of a quinazoline based structure. Terazosin significantly inhibited vascular endothelial growth factor induced angiogenesis in nude mice with an IC50 of 7.9 microM., showing that it had a more potent anti-angiogenic than cytotoxic effect. Terazosin also effectively inhibited vascular endothelial growth factor induced proliferation and tube formation in cultured human umbilical vein endothelial cells (IC50 9.9 and 6.8 microM., respectively).
Together our data suggest that terazosin shows direct anti-angiogenic activity through the inhibition of proliferation and tube formation in endothelial cells. This action may partly explain the in vivo antitumor potential of terazosin.
有研究表明特拉唑嗪对前列腺肿瘤生长具有抑制作用。我们旨在确定特拉唑嗪的作用是否有助于直接抑制血管生成效应。
本研究使用了PC-3细胞和人良性前列腺细胞原代培养物。采用3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐法和乳酸脱氢酶释放反应检测细胞毒性。在裸鼠模型中测定体内血管生成效应，随后进行组织学检查并通过血红蛋白检测法进行定量。在培养的人脐静脉内皮细胞中进行细胞迁移、增殖和管形成的体外测定。结果：特拉唑嗪对PC-3细胞和人良性前列腺细胞具有细胞毒性，IC50大于100μM。阳性末端脱氧核苷酸转移酶脱氧尿苷三磷酸缺口末端标记和乳酸脱氢酶释放反应与特拉唑嗪诱导的细胞毒性相关，表明细胞发生凋亡和坏死性死亡。此外，特拉唑嗪作用引起的细胞毒性并非基于喹唑啉结构的共同特征。特拉唑嗪显著抑制裸鼠体内血管内皮生长因子诱导的血管生成，IC50为7.9μM，表明其抗血管生成作用比细胞毒性作用更强。特拉唑嗪还有效抑制培养的人脐静脉内皮细胞中血管内皮生长因子诱导的增殖和管形成（IC50分别为9.9和6.8μM）。
我们的数据共同表明，特拉唑嗪通过抑制内皮细胞的增殖和管形成表现出直接的抗血管生成活性。这一作用可能部分解释了特拉唑嗪在体内的抗肿瘤潜力。
