Michio Kosugi

Angiotensin II type 1 receptor antagonist candesartan as an angiogenic inhibitor in a xenograft model of bladder cancer.

Purpose: 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. Experimental Design: 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. Results: 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/103 cells) than in the angiotensin II–treated control cells (3.16 ± 0.42 and 7.91 ± 0.69 pg/103 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. Conclusions: 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.

Effect of angiotensin II type 1 receptor antagonist on tumor growth and angiogenesis in a xenograft model of human bladder cancer

Several authors have investigated the antitumor activity of angiotensin II type 1 receptor (AT1 R) antagonists, which are widely used as antihypertensive drugs. In this study, we evaluated the efficacy of the AT1 R antagonist candesartan against bladder cancer. For the study in vitro, human bladder cancer cells (KU-19-19) were cultured with and without angiotensin II (A II) and candesartan, and cell viability and vascular endothelial growth factor (VEGF) secretion were analyzed. Also for the study in vivo, a tumor xenograft model was prepared in nude mice using KU-19-19 cells. Mice were administered candesartan daily by oral gavage, and paclitaxel via intravenous infusion. Microvessel density, VEGF expression, and apoptosis were investigated. Candesartan did not induce direct toxicity in KU-19-19 cells, but VEGF was significantly lower in candesartan-treated cells than in the A II-treated control cells. In mice, candesartan, paclitaxel and candesartan-paclitaxel significantly suppressed tumor growth to 46.0%, 35.8% and 17.3%, respectively, of the tumor volume in the control group, showing that combined treatment significantly inhibited tumor growth compared to the candesartan group. Microvessel density and VEGF were significantly decreased in the candesartan and candesartan-paclitaxel groups compared to the control group. The apoptotic index was significantly increased in the paclitaxel and candesartan-paclitaxel groups compared to the control and candesartan groups. In our experimental model, candesartan prevented bladder cancer growth by inhibiting angiogenesis. Furthermore, combined treatment with candesartan and paclitaxel enhanced paclitaxel-induced cytotoxicity. These results suggest that the AT1 R antagonist candesartan may be a candidate for innovative therapy for bladder cancer.

Angiotensin II Type 1 Receptor Antagonist Enhances Cis-dichlorodiammineplatinum-Induced Cytotoxicity in Mouse Xenograft Model of Bladder Cancer

OBJECTIVES To examine whether candesartan enhances the cytotoxicity of cis-dichlorodiammineplatinum (CDDP) in mice with bladder cancer as a method to enhance the therapeutic effects of CDDP. CDDP is an antitumor agent conventionally used against bladder cancer; however, its therapeutic efficacy appears to not be fully satisfactory. Recent studies have shown the antitumor activity of the angiotensin II type 1 receptor antagonist candesartan. METHODS A xenograft model was prepared in nude mice using human bladder cancer cells (KU-19-19). Candesartan (1 mg/kg/d) was administered daily by oral gavage from the day of implantation plus 28 days, and CDDP (1 mg/kg/d) was administered intraperitoneally from days 5 to 9. The microvessel density, vascular endothelial growth factor expression, and apoptosis were investigated immunohistochemically. RESULTS Candesartan, CDDP, and candesartan-CDDP suppressed tumor growth to 41.9%, 33.8%, and 13.2%, respectively, of the tumor volume in the control group, showing that combined treatment significantly inhibited tumor growth compared with each single agent alone. The microvessel density was significantly decreased in the candesartan and candesartan-CDDP groups compared with the control group. Vascular endothelial growth factor expression was significantly decreased in the candesartan, CDDP, and candesartan-CDDP groups compared with the control group. The apoptotic index was significantly increased in the CDDP and candesartan-CDDP groups compared with the control and candesartan groups. CONCLUSIONS It is quite likely that candesartan and CDDP suppressed tumor growth by inhibiting angiogenesis and inducing apoptosis, respectively. Furthermore, combined treatment with candesartan enhanced CDDP-induced cytotoxicity by further suppressing angiogenesis. These results suggest that candesartan could be a candidate for innovational therapy of bladder cancer.

Tumour length of the largest focus predicts prostate-specific antigen-based recurrence after radical prostatectomy in clinically localized prostate cancer.

To investigate the possible significance of tumour dimensional variables, including maximum tumour diameter (MTD), maximum tumour area (MTA) and total tumour volume (TTV), with standard prognostic factors for predicting prostate‐specific antigen (PSA) recurrence after radical prostatectomy (RP).

Potent Cytotoxic Effect of a Novel Nuclear Factor-κB Inhibitor Dehydroxymethylepoxyquinomicin on Human Bladder Cancer Cells Producing Various Cytokines

OBJECTIVES To explore the potential therapeutic effects of the nuclear factor-kappaB (NF-kappaB) inhibitor dehydroxymethylepoxyquinomicin (DHMEQ). KU-19-19 cells, originally derived from a patient with invasive bladder cancer who exhibited marked leukocytosis, produce multiple cytokines. This model of clinically advanced bladder cancer, in which NF-kappaB is constitutively activated, was used in this study. METHODS Expression of p65 protein in fractionated KU-19-19 cells was determined by Western blotting analysis. DNA-binding activity of NF-kappaB was detected by electrophoretic mobility shift assay. The cytotoxic effects and induction of apoptosis by DHMEQ were analyzed, and cytokines in the supernatant of KU-19-19 cells cultured with or without DHMEQ were measured by enzyme-linked immunosorbent assay (ELISA). Athymic nude mice bearing KU-19-19 subcutaneous tumors were subjected to intraperitoneal administration of 2 mg/kg/d DHMEQ for 3 weeks. Tumor growth was monitored and microvessel density, vascular endothelial growth factor expression, and the apoptotic index of tumors were evaluated by tissue immunohistochemistry. RESULTS NF-kappaB was constitutively activated in KU-19-19 cells. DHMEQ reversibly inhibited the DNA-binding activity of NF-kappaB by blocking its nuclear translocation. Both cell viability and production of cytokines were significantly and dose-dependently suppressed by DHMEQ, and significant apoptosis was also induced. In in vivo studies, the mean tumor volume in mice treated with DHMEQ was significantly smaller than in controls. Immunohistochemical analysis of tumors revealed marked reduction in microvessel density, vascular endothelial growth factor expression, and induction of apoptosis. CONCLUSIONS Blockade of NF-kappaB function by DHMEQ may be a useful new molecular targeting treatment for highly aggressive bladder cancer.