Gee Jason R, Saltzstein Daniel R, Kim KyungMann, Kolesar Jill, Huang Wei, Havighurst Thomas C, Wollmer Barbara W, Stublaski Jeanne, Downs Tracy, Mukhtar Hasan, House Margaret G, Parnes Howard L, Bailey Howard H
Institute of Urology, Lahey Hospital and Medical Center, Burlington, Massachusetts.
Urology San Antonio Research, University of Wisconsin-Madison, Madison, Wisconsin.
Cancer Prev Res (Phila). 2017 May;10(5):298-307. doi: 10.1158/1940-6207.CAPR-16-0167. Epub 2017 Mar 21.
We performed a phase II pharmacodynamic prevention trial of Polyphenon E [a green tea polyphenol formulation primarily consisting of epigallocatechin gallate (EGCG)] in patients prior to bladder cancer surgery. Patients with a bladder tumor were randomized to receive Polyphenon E containing either 800 or 1,200 mg of EGCG or placebo for 14 to 28 days prior to transurethral resection of bladder tumor or cystectomy. The primary objective was to compare the postintervention EGCG tissue levels in patients receiving Polyphenon E as compared with placebo. Secondary objectives included assessments of tissue expression of PCNA, MMP2, clusterin, VEGF, p27, IGF-1, IGFBP-3; correlation of tissue, plasma, and urine levels of EGCG; and EGCG metabolism by catechol-O-methyltransferase and UDP-glucuronosyltransferase pharmacogenomic mutations. Thirty-one patients (male:female, 26:5; mean age, 67.2 years) were randomized and 29 (94%) completed the study. There was not an observed significant difference ( = 0.12) in EGCG tissue levels between two Polyphenon E dosage groups combined versus placebo. However, a dose-response relationship for EGCG levels was observed in both normal ( = 0.046) and malignant bladder tissue ( = 0.005) across the three study arms. In addition, EGCG levels in plasma ( < 0.001) and urine ( < 0.001) increased and PCNA ( = 0.016) and clusterin ( = 0.008) were downregulated in a dose-dependent fashion. No pharmacogenomic relationship was observed. EGCG levels in plasma, urine, and bladder tissue followed a dose-response relationship, as did modulation of tissue biomarkers of proliferation and apoptosis. Despite the limitations of this pilot study, the observed pharmacodynamics and desirable biologic activity warrant further clinical studies of this agent in bladder cancer prevention. .
我们在膀胱癌手术前的患者中开展了一项关于表没食子儿茶素没食子酸酯（EGCG）为主的绿茶多酚制剂Polyphenon E的II期药效学预防试验。膀胱肿瘤患者被随机分为三组，在经尿道膀胱肿瘤切除术或膀胱切除术之前的14至28天，分别接受含800毫克或1200毫克EGCG的Polyphenon E或安慰剂。主要目的是比较接受Polyphenon E的患者与接受安慰剂的患者干预后EGCG的组织水平。次要目的包括评估增殖细胞核抗原（PCNA）、基质金属蛋白酶2（MMP2）、簇集蛋白、血管内皮生长因子（VEGF）、p27、胰岛素样生长因子1（IGF-1）、胰岛素样生长因子结合蛋白3（IGFBP-3）的组织表达；EGCG组织、血浆和尿液水平的相关性；以及儿茶酚-O-甲基转移酶和尿苷二磷酸葡萄糖醛酸基转移酶药物基因组突变对EGCG代谢的影响。31名患者（男:女为26:5；平均年龄67.2岁）被随机分组，29名（94%）完成了研究。联合的两个Polyphenon E剂量组与安慰剂组相比，EGCG组织水平未观察到显著差异（P = 0.12）。然而，在三个研究组中，正常膀胱组织（P = 0.046）和恶性膀胱组织（P = 0.005）中均观察到EGCG水平呈剂量反应关系。此外，血浆（P < 0.001）和尿液（P < 0.001）中的EGCG水平升高，PCNA（P = 0.016）和簇集蛋白（P = 0.008）呈剂量依赖性下调。未观察到药物基因组学关系。血浆、尿液和膀胱组织中的EGCG水平呈剂量反应关系，增殖和凋亡的组织生物标志物的调节也是如此。尽管这项初步研究存在局限性，但观察到的药效学和理想的生物学活性值得对该药物在膀胱癌预防方面进行进一步的临床研究。
