In Vivo Molecular Effects of Prostatic COX-2 Inhibition

描述(由申请人提供)： 该提案阐述了药物抑制环氧合酶-2酶(COX-2)在前列腺癌预防或治疗中的潜在作用，体外实验研究有令人信服的证据表明，抑制COX-2可抑制细胞增殖，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，使用非类固醇抗炎药COX-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作用的理论之一是通过保护活性氧物种和随后的DNA损伤，而另一些理论则假设这些药物调节细胞周期。目前有几个小组正在继续深入研究不同的COX-2抑制剂对CAP细胞系或CAP异种移植瘤的体外作用，然而，还没有人的实验研究考察COX-2抑制剂对前列腺组织生物学的影响，这一建议是基于这样的假设：抑制COX-2将减少前列腺素水平，减少氧化应激，并调节前列腺组织中控制细胞周期的基因。这一假设将在两个双盲、安慰剂对照的随机临床试验中得到验证，以测试25毫克的环氧合酶-2抑制剂罗非昔布(Vioxx())对前列腺生物学的影响：第一个试验是在癌症活检呈阳性的男性中，计划在6周内进行前列腺癌切除术；第二个试验是在前列腺癌活检阴性的男性中，计划在6个月后再次进行活检。最初活检时收集的组织和血液将与治疗后收集的组织和血液进行比较，从而评估COX-2抑制的急性(4周)和慢性(6个月)影响。所有分析都基于对治疗干预效果的建模，其定义为在活性药物组减去安慰剂组的情况下，癌症相关终点测量从基线到随访的变化。这些研究的结果将阐明COX-2抑制对前列腺癌生物学的影响，揭示COX-2抑制剂对前列腺癌风险影响的潜在机制，并为未来的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.