Phase II Clinical Trial of Polyphenon E in Prostate Cancer

流行病学和实验室研究已经在绿色茶中发现了表没食子儿茶素没食子酸酯（EGCG 多酚（GTP）是诱导细胞凋亡的最有效的化学预防剂， 包括前列腺癌（CaP）在内的人类癌症的形成和生长。我们的研究小组已经证明， 和Polyphenon E，有效地和选择性地抑制完整人胰凝乳蛋白酶样蛋白酶体活性 CaP细胞，因此积累IkB-？和p27蛋白，导致生长停滞。的 GTP的几种制剂的药代动力学和安全性，特别是Polyphenon E，剂量范围为 600-1200毫克的EGCG已在I期试验中得到证实。在一项初步研究中，Bettuzzi等人26， 在60名男性中证实了GTP（400 mg EGCG/天）用于化学预防CaP的安全性和有效性 诊断为HGPIN的患者中，GTP治疗的男性中只有1例诊断为肿瘤（3%），而 安慰剂治疗组的癌症（30%）。基于我们和其他人的研究成果， 包括Bettuzzi等人的结果，这是一项确定的II期临床试验，旨在检查表没食子儿茶素没食子酸酯在 在诊断为HGPIN病变的较大队列中抑制向CaP的进展是合乎逻辑的下一步。的 拟议的II期临床试验的中心假设是，接受Polyphenon E治疗的HGPIN患者 400 mg EGCG/天的剂量持续12个月将显著降低进展为CaP， 服用安慰剂的HGPIN患者。我们假设茶儿茶素， 特别是EGCG会诱导前列腺上皮细胞凋亡，是通过蛋白酶体抑制途径， 导致前列腺细胞存活的抑制和细胞凋亡的诱导，从而减少从 HGPIN与前列腺癌的关系。为了验证这一假设，我们的具体目标将是招募，随机化和治疗 240名（120名男性/组）诊断为HGPIN的男性接受含400 mg EGCG的Polyphenon E或 安慰剂治疗一年，评估依从性、症状、毒性，评估HGPIN和前列腺癌 6个月和12个月时的发生率以及处理相关的蛋白酶体活性抑制和细胞凋亡诱导 在前列腺组织活检中。我们的另一个目标是探索其他潜在的机制， EGCG和GTP的基本分子途径模型。我们的建议是创新的，及时的， 提供了一种可靠的方法来评估一种有前途的基于营养素的化学预防剂， 重大公共卫生疾病。如果Polyphenon E用于化学预防的安全性和效果 我们计划在一个大型的III期试验中检查这种药物的长期效果。项目叙述： 该项目的具体目标是招募、随机化和治疗240名（120名男性/组）诊断为 HGPIN接受含有400 mg EGCG或安慰剂的Polyphenon E治疗一年，并评估依从性， 症状、毒性、评估6个月和12个月时的HGPIN和前列腺癌发生率以及治疗相关性 前列腺组织活检中蛋白酶体活性抑制和细胞凋亡诱导。我们的另一个目标是 探索其他潜在的机制，以开发和完善EGCG的基本分子途径模型 和GTP。

Epidemiological and laboratory studies have identified epigallocatechin gallate (EGCG) in green tea polyphenols (GTP), as the most potent chemopreventive agent that can induce apoptosis, suppress the formation and growth of human cancers including prostate cancer (CaP). Our group has shown that EGCG and Polyphenon E, potently and selectively inhibits the proteasomal chymotrypsin-like activities in intact human CaP cells and consequently accumulates IkB-? and p27 proteins, leading to growth arrest. The pharmacokinetics and safety of several preparations of GTP, specifically Polyphenon E at doses ranging from 600-1200 mgs EGCG have been demonstrated in phase I trials. In a preliminary study, Bettuzzi et al 26, demonstrated the safety and efficacy of GTPs (400 mgs of EGCG/day) for chemoprevention of CaP in 60 men diagnosed with HGPIN, with only 1 tumor diagnosed among the GTP-treated men (3%), compared to 9 cancers in the placebo-treated arm (30%). Based on the promising results of our studies and that of others, including Bettuzzi et al's results, a definitive phase II clinical trial, powered to examine the effects of EGCG in inhibiting the progression to CaP in larger cohort diagnosed with HGPIN lesions, is a logical next step. The central hypothesis for the proposed phase II clinical trial is that men with HGPIN who receive Polyphenon E at a dose of 400 mg EGCG/day for 12 months will significantly decrease progression to CaP compared with men with HGPIN who take placebo. We hypothesize that the primary pathway by which tea catechins, specifically EGCG will induce prostate epithelial cell apoptosis, is via the proteasome inhibition pathway, resulting in inhibition of prostate cell survival and induction of apoptosis, thereby decreasing progression from HGPIN to prostate cancer. To test this hypothesis, our specific aims will be to recruit, randomize and treat 240 (120 men/arm) men diagnosed with HGPIN to receive Polyphenon E containing 400 mg of EGCG or placebo for one year and evaluate compliance, symptoms, toxicity, evaluate HGPIN and prostate cancer incidence at 6 and 12 months and treatment-related inhibition of proteasome activity and induction of apoptosis in prostate tissue biopsies. Our other aim is to explore other potential mechanisms to develop and refine models of fundamental molecular pathways for EGCG and GTP. Our proposal is innovative, timely, and provides a robust approach to evaluate a promising nutrient-based chemopreventive agent against a disease of major public health significance. If the safety and the effects of Polyphenon E for chemoprevention of CaP are demonstrated, we plan to then examine the long-term effects of this agent in a large Phase III trial. Project Narrative: The specific aims of this project will be to recruit, randomize and treat 240 (120 men/arm) men diagnosed with HGPIN to receive Polyphenon E containing 400 mg of EGCG or placebo for one year and evaluate compliance, symptoms, toxicity, evaluate HGPIN and prostate cancer incidence at 6 and 12 months and treatment-related inhibition of proteasome activity and induction of apoptosis in prostate tissue biopsies. Our other aim is to explore other potential mechanisms to develop and refine models of fundamental molecular pathways for EGCG and GTP.