In Vivo Molecular Effects of Prostatic COX-2 Inhibition

描述（由申请人提供）： 该提案提出了药理学抑制环氧合酶-2酶（考克斯-2）对前列腺癌预防或治疗的潜在作用。体外实验研究有令人信服的证据表明，抑制考克斯-2可降低细胞增殖，增加细胞凋亡，并调节参与细胞周期调控的基因。此外，观察性流行病学研究发现，使用非甾体抗炎药、考克斯-2抑制剂的男性患前列腺癌的风险降低。关于这些化合物如何发挥其作用的理论之一是通过保护免受活性氧和随后的DNA损伤，而其他人则假设这些药物调节细胞周期。几个小组目前正在继续深入研究各种考克斯-2抑制剂对CaP细胞系或CaP异种移植物的体外作用，然而，没有人实验研究已经研究了考克斯-2抑制剂对前列腺组织生物学的作用。该提议基于以下假设：考克斯-2抑制将降低前列腺内前列腺素的水平，减少氧化应激，并调节控制前列腺组织细胞周期的基因。这一假设将在两项双盲、安慰剂对照、随机临床试验中进行检验，以测试25 mg考克斯-2抑制剂罗非昔布（万络）对前列腺生物学的影响：第一项试验在6周内计划进行前列腺切除术的癌症活检阳性男性中进行;第二项试验在6个月内计划进行重复活检的前列腺活检阴性男性中进行。将在初始活检时收集的组织和血液与治疗后收集的组织和血液进行比较，以评估考克斯-2抑制的急性（4周）和慢性（6个月）效应。所有分析均基于对治疗干预效应的建模，定义为活性药物组减去安慰剂组中癌症相关终点指标从基线至随访的变化。这些研究的结果将阐明考克斯-2抑制剂对前列腺生物学的影响，揭示考克斯-2抑制剂对前列腺癌风险影响的潜在机制，并为未来的初级和二级前列腺癌预防试验确定其他途径和靶点。

DESCRIPTION (provided by applicant): The proposal addresses the potential role of pharmacologic inhibition of the cyclooxygenase-2 enzyme (COX-2) for prostate cancer prevention or treatment, There is compelling evidence from in vitro experimental studies that inhibition of COX-2 decreases cellular proliferation, increases apoptosis, and modulates genes involved in cell cycle regulation. Additionally, observational epidemiologic studies find reduced risks of prostate cancer among men using nonsteroidal anti-inflammatory drugs, COX-2 inhibitors. One of the theories on how these compounds exert their effects is through protection from reactive oxygen species and subsequent DNA damage, while others have postulated that these agents modulate the cell cycle. Several groups currently are continuing intensive studies examining the in vitro effects of various COX-2 inhibitors on CaP cell lines or in CaP xenografts, however, no human experimental studies have examined the effects of COX-2 inhibitors on prostate tissue biology, This proposal is based on the hypothesis that COX-2 inhibition will reduce levels of intraprostatic prostaglandins, reduce oxidative stress, and modulate genes controlling the cell cycle in prostate tissue. The hypothesis will be tested in two double-blinded, placebo-controlled, randomized clinical trials to test effects of 25mg of the COX-2 inhibitor rofecoxib (Vioxx() on prostate biology: the first among men with a biopsy positive for cancer scheduled for prostatectomy within 6 weeks; the second among men with a prostate biopsy negative for cancer scheduled for repeat biopsy in 6 months. Tissues and blood collected at the initial biopsy will be compared with those collected post-treatment, allowing an assessment of both the acute (4 weeks) and chronic (6 months) effects of COX-2 inhibition. All analyses are based on modeling the treatment intervention effect, defined as the changes in cancer-related endpoint measures from baseline to follow-up in the active drug arm minus the placebo arm. The results of these investigations will clarify the impact of COX-2 inhibition on prostate biology, reveal mechanisms underlying the effects of COX-2 inhibitors on prostate cancer risk, and identify other pathways and targets for future primary and secondary prostate cancer prevention trials.