In vivo effects of sulforaphane supplementation on normal human prostate

描述(由申请人提供)： 这项建议的总体目标是使用一种新的活体人类干预模型来了解萝卜硫素(十字花科蔬菜中的活性化合物)在人类前列腺中的活性，因为这些活性植物化合物被认为与前列腺癌风险有关。几项大型、精心设计的流行病学研究发现，经常食用十字花科甘蓝属蔬菜与降低前列腺癌风险有关。此外，来自体外和实验动物研究以及有限数量的人类喂养研究的充分证据表明，这些化合物的代谢物诱导II相解毒酶，减少癌症生长，并调节氧化应激。然而，十字花科蔬菜中的活性化合物对人前列腺的体内作用尚不清楚。在这里，我们提出了一项随机、双盲、安慰剂对照的临床试验，以评估高硫萝卜素、西兰花芽提取物对人前列腺组织的体内影响。我们将随机选择100名患有局限性低级别前列腺癌的男性患者，并使用在诊断(活检)和前列腺切除术时收集的前列腺组织来评估精心选择和评估的措施，包括II期解毒酶诱导、前列腺内类固醇激素代谢、氧化损伤和前列腺癌细胞的生长。主要的具体目的是测试西兰花芽提取物是否：(1)诱导人体前列腺的抗氧化反应，减少氧化损伤；(2)增加DHT的分解代谢，降低前列腺内的双氢睾酮(DHT)浓度。第二个目标将检查：(1)高硫萝卜素西兰花芽提取物是否影响与前列腺癌发展和/或早期进展相关的途径，以及(2)GSTM1基因是否改变对高硫萝卜素西兰花芽提取物的反应。我们希望在人类身上证实在动物和体外模型中检测萝卜硫素的研究结果，这将是我们在饮食预防前列腺癌方面的重要进展。我们认为萝卜硫素很可能是前列腺癌的有效预防药物，而且评估十字花科化合物对人类的影响的研究是有良好动机的。公共卫生相关性：项目叙述前列腺癌是男性中最常见的癌症，也是美国男性癌症死亡的第二大原因。饮食改变干预，或使用从食物中提取的生物活性化合物，是一种特别有吸引力的前列腺癌预防方法，因为它们成本低，毒性低，并且没有不良事件。在向男性提供前列腺癌的公共卫生建议之前，需要更好地了解这些药物的潜在机制和有效性。这项西兰花中活性化合物的随机试验可能会为预防美国男性最常见的癌症提供一种重要的、成本效益高、不良事件发生率低的方法。

DESCRIPTION (provided by applicant): The overall goal of this proposal is to use a novel in vivo human intervention model to understand the activities of sulforaphane (the bioactive compound in Brassica vegetables) in human prostate since these bioactive plant compounds are believed to be associated with prostate cancer risk. Several large, well-designed epidemiological studies have found that regular consumption of vegetables in the Brassica oleracea (Cruciferae) family is associated with reduced prostate cancer risk. Further, there is ample evidence from in vitro and experimental animal studies, along with a limited number of human feeding studies, that metabolites of the these compounds induce phase II detoxification enzymes, decrease cancer growth, and modulate oxidative stress. However, the in vivo effects of the bioactive compounds in Brassica vegetables on human prostate are unknown. Here we propose a randomized, double-blinded, placebo-controlled clinical trial to evaluate the in vivo effects of a high-sulforaphane, broccoli sprout extract on human prostate tissue. We will randomize 100 men with localized, low-grade prostate cancer, and use prostate tissue collected at both the time of diagnosis (biopsy) and prostatectomy to assess carefully selected and evaluated measures of phase II detoxifying enzyme induction, intra-prostatic steroid hormone metabolism, oxidative damage, and growth of prostate cancer cells. The Primary Specific Aims are to test whether the broccoli sprout extract: (1) induces an antioxidant response and reduces oxidative damage in human prostate and (2) increases DHT catabolism and reduces intra-prostatic dihydrotestosterone (DHT) concentration. Secondary Aims will examine: (1) whether the high-sulforaphane broccoli sprout extract affects pathways associated with development and/or early progression of prostate cancer and (2) whether GSTM1 genotype modifies responses to the high- sulforaphane broccoli sprout extract. We hope to confirm in humans the findings from studies examining sulforaphane in animal and in vitro models, which would be an important advance in our work toward the dietary prevention of prostate cancer. We believe it is likely that sulforaphane could be an effective preventive agent for prostate cancer, and that research to evaluate the effects of Brassica compounds in humans is well motivated. PUBLIC HEALTH RELEVANCE: Project Narrative Prostate cancer is the most commonly diagnosed cancer among men as well as the second leading cause of male cancer deaths in the United States. Dietary change interventions, or use of bioactive compounds derived from food, are an especially appealing approach to prostate cancer prevention due to their low cost, low toxicity, and absence of adverse events. Before public health recommendations for prostate cancer can be offered to men, a better understanding of the potential mechanisms, as well as efficacy of the agents is needed. This randomized trial of bioactive compounds in broccoli may provide an important, cost-effective, low-adverse-event means of prevention of the most common cancer in US males.