Kosugi Michio, Miyajima Akira, Kikuchi Eiji, Horiguchi Yutaka, Murai Masaru
Department of Urology, Keio University School of Medicine, Shinanomachi, Tokyo, Japan.
Clin Cancer Res. 2006 May 1;12(9):2888-93. doi: 10.1158/1078-0432.CCR-05-2213.
There have been several studies on the antitumor activity of angiotensin II type 1 receptor (AT1R) antagonists. In this study, we evaluated the efficacy of the AT1R antagonist candesartan in bladder cancer.
For the study in vitro, human bladder cancer cells (KU-19-19) were cultured with or without angiotensin II and candesartan. Various cytokines and cell viability were analyzed. For the study in vivo, a tumor xenograft model was prepared in nude mice using KU-19-19 cells. Mice were given candesartan daily by oral gavage. Microvessel density, expression of vascular endothelial growth factor (VEGF), and apoptosis were assessed.
Candesartan did not induce direct toxicity in KU-19-19 cells, but VEGF and interleukin-8 were significantly lower in candesartan-treated cells (2.55 +/- 0.25 and 6.58 +/- 0.48 pg/10(3) cells) than in the angiotensin II-treated control cells (3.16 +/- 0.42 and 7.91 +/- 0.69 pg/10(3) cells). In mice, candesartan both at doses of 2 and 10 mg/kg/d significantly suppressed tumor growth in mice (35.4% and 33.5% reduction in tumor volume). Microvessel density was significantly decreased by candesartan (9.8 +/- 2.8 per field) compared with the control group (17.6 +/- 6.0 per field), and VEGF expression was significantly suppressed by this AT1R antagonist. However, candesartan did not induce apoptosis of cancer cells in the tumor.
Specific blockade of AT1R prevented bladder tumor growth by inhibiting angiogenesis. However, its antitumor effect was not due to direct toxicity. Because AT1R antagonists are widely used to treat hypertension, and a 2 mg/kg/d dose level of candesartan is clinically achievable, this AT1R antagonist could also be used to treat bladder cancer.
已有多项关于血管紧张素II 1型受体（AT1R）拮抗剂抗肿瘤活性的研究。在本研究中，我们评估了AT1R拮抗剂坎地沙坦在膀胱癌中的疗效。
在体外研究中，将人膀胱癌细胞（KU-19-19）在有或无血管紧张素II及坎地沙坦的情况下进行培养。分析各种细胞因子和细胞活力。在体内研究中，使用KU-19-19细胞在裸鼠中制备肿瘤异种移植模型。通过口服灌胃每日给小鼠给予坎地沙坦。评估微血管密度、血管内皮生长因子（VEGF）的表达及细胞凋亡情况。
坎地沙坦对KU-19-19细胞未诱导直接毒性，但与血管紧张素II处理的对照细胞（3.16±0.42和7.91±0.69 pg/10³细胞）相比，坎地沙坦处理的细胞中VEGF和白细胞介素-8显著降低（2.55±0.25和6.58±0.48 pg/10³细胞）。在小鼠中，剂量为2和10 mg/kg/d的坎地沙坦均显著抑制小鼠肿瘤生长（肿瘤体积分别减少35.4%和33.5%）。与对照组（每视野17.6±6.0）相比，坎地沙坦使微血管密度显著降低（每视野9.8±2.8），且该AT1R拮抗剂显著抑制VEGF表达。然而，坎地沙坦未诱导肿瘤中癌细胞的凋亡。
AT1R的特异性阻断通过抑制血管生成阻止膀胱肿瘤生长。然而，其抗肿瘤作用并非由于直接毒性。由于AT1R拮抗剂广泛用于治疗高血压，且临床可达到2 mg/kg/d的坎地沙坦剂量水平，因此该AT1R拮抗剂也可用于治疗膀胱癌。
