Buckley Michael T, Yoon Joanne, Yee Herman, Chiriboga Luis, Liebes Leonard, Ara Gulshan, Qian Xiaozhong, Bajorin Dean F, Sun Tung-Tien, Wu Xue-Ru, Osman Iman
Urology, New York University School of Medicine, New York, USA.
J Transl Med. 2007 Oct 12;5:49. doi: 10.1186/1479-5876-5-49.
Treatment options for patients with recurrent superficial bladder cancer are limited, necessitating aggressive exploration of new treatment strategies that effectively prevent recurrence and progression to invasive disease. We assessed the effects of belinostat (previously PXD101), a novel histone deacetylase inhibitor, on a panel of human bladder cancer cell lines representing superficial and invasive disease, and on a transgenic mouse model of superficial bladder cancer.
Growth inhibition and cell cycle distribution effect of belinostat on 5637, T24, J82, and RT4 urothelial lines were assessed. Ha-ras transgenic mice with established superficial bladder cancer were randomized to receive either belinostat or vehicle alone, and assessed for bladder weight, hematuria, gene expression profiling, and immunohistochemistry (IHC).
Belinostat had a significant linear dose-dependent growth inhibition on all cell lines (IC50 range of 1.0-10.0 microM). The 5637 cell line, which was derived from a superficial papillary tumor, was the most sensitive to treatment. Belinostat (100 mg/kg, intraperitoneal, 5 days each week for 3 weeks) treated mice had less bladder weight (p < 0.05), and no hematuria compared with 6/10 control mice that developed at least one episode. IHC of bladder tumors showed less cell proliferation and a higher expression of p21WAF1 in the belinostat-treated mice. Gene expression profile analysis revealed 56 genes significantly different in the treated group; these included the upregulation of p21WAF1, induction of core histone deacetylase (HDAC), and cell communication genes.
Our data demonstrate that belinostat inhibits bladder cancer and supports the clinical evaluation of belinostat for the treatment of patients with superficial bladder cancer.
复发性浅表性膀胱癌患者的治疗选择有限，因此有必要积极探索能有效预防复发和进展为浸润性疾病的新治疗策略。我们评估了新型组蛋白去乙酰化酶抑制剂贝利司他（先前称为PXD101）对一组代表浅表性和浸润性疾病的人膀胱癌细胞系以及对浅表性膀胱癌转基因小鼠模型的影响。
评估了贝利司他对5637、T24、J82和RT4尿路上皮细胞系的生长抑制和细胞周期分布效应。将已患浅表性膀胱癌的Ha-ras转基因小鼠随机分组，分别接受贝利司他或单独的赋形剂，并评估膀胱重量、血尿、基因表达谱和免疫组织化学（IHC）。
贝利司他对所有细胞系均有显著的线性剂量依赖性生长抑制作用（IC50范围为1.0 - 10.0 microM）。源自浅表乳头状肿瘤的5637细胞系对治疗最为敏感。与6/10出现至少一次血尿的对照小鼠相比，接受贝利司他（100 mg/kg，腹腔注射，每周5天，共3周）治疗的小鼠膀胱重量较轻（p < 0.05）且无血尿。膀胱肿瘤的免疫组织化学显示，在接受贝利司他治疗的小鼠中细胞增殖较少且p21WAF1表达较高。基因表达谱分析显示治疗组中有56个基因存在显著差异；这些基因包括p21WAF1的上调、核心组蛋白去乙酰化酶（HDAC）的诱导以及细胞通讯基因。
我们的数据表明贝利司他可抑制膀胱癌，并支持对贝利司他用于治疗浅表性膀胱癌患者进行临床评估。
