Prostate-Directed Antioxidant to Prevent Prostate Cancer

前列腺定向抗氧化剂可预防前列腺癌

• 批准号: 7102305
• 负责人: Hirak S. Basu
• 金额: $ 7.35万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7102305
• 关键词: androgens; antioxidants; neoplasm /cancer; neoplastic cell; oxidation; oxidative stress; polyamines; prostate; prostate neoplasms

DESCRIPTION (provided by applicant): Advanced hormone refractory metastatic prostate cancer is the second leading cause of cancer deaths among US men. As commonly used chemotherapeutic agents have limited success in the treatment of prostate cancer, development of novel agents to prevent its occurrence and progression is urgently needed. Reactive oxygen species (ROS) such as hydrogen peroxide, superoxide, hydroxyl free radical and nitric oxide levels are relatively higher in prostate tumors than in normal tissues. In the past 5 years, direct evidence linking ROS with an increase in tumor development in various tissues including that in the prostate has been reported. It has also been demonstrated that androgen modulates ROS production in androgen dependent prostate cancer cells. Although the exact mechanism of ROS production remains unknown, one possibility may be through the induction of the polyamine catabolic pathway as prostate cells produce a large excess of polyamines. Polyamines catabolize through acetylation by spermidine/spermine acetyltransferase (SSAT) followed by oxidation by acetyl polyamine oxidase (APAO) that produces ROS. Recent DNA microarray analysis and qRT-PCR studies carried out in our laboratory have shown that androgen induces overexpression of the SSAT gene in androgen dependent prostate cancer cells. Our preliminary data showed that pretreatment of androgen dependent LNCaP cells with an APAO inhibitor MDL completely abrogates androgen induced oxidative stress. Here, we propose to develop MDL that specifically reduces oxidative stress in prostate cells as an agent that can prevent occurrence, growth and/or progression of prostate cancer. Our specific aims are: 1) To establish the ability of MDL pretreatment to block androgen induced oxidative stress in androgen dependent prostate cancer cell lines LapC4 and LNCaP by dichlorofluorescene (DCF) oxidation assay. 2) To determine the ability of MDL to reduce oxidative stress in LNCaP tumor xenografts in nude mouse model using Hydroethidine (HEt) oxidation method. 3) To determine the ability of MDL to prevent growth of LNCaP and LapC4 tumor xenografts in nude mouse. 4) To determine the ability of MDL to prevent spontaneous prostate tumor formation in transgenic adenocarcinoma in mouse prostate (TRAMP) model. A successful completion of these Aims will not only establish MDL as a potential prostate cancer chemopreventive agent that can be further developed for clinical use but should also demonstrate the importance of polyamine catabolic pathway as a valid target for prostate cancer chemoprevention.

描述（由申请人提供）：晚期激素难治性转移性前列腺癌是美国男性癌症死亡的第二大原因。由于常用的化疗药物在治疗前列腺癌方面效果有限，因此迫切需要开发新的药物来预防其发生和进展。前列腺肿瘤中的活性氧（ROS），如过氧化氢、超氧化物、羟基自由基和一氧化氮水平相对高于正常组织。在过去的 5 年里，有直接证据表明 ROS 与包括前列腺在内的各种组织中肿瘤发展的增加有关。研究还表明，雄激素可调节雄激素依赖性前列腺癌细胞中 ROS 的产生。尽管ROS产生的确切机制仍不清楚，但一种可能性可能是通过诱导多胺分解代谢途径，因为前列腺细胞产生大量过量的多胺。多胺通过亚精胺/精胺乙酰转移酶 (SSAT) 乙酰化进行分解代谢，然后被乙酰多胺氧化酶 (APAO) 氧化，产生 ROS。我们实验室最近进行的 DNA 微阵列分析和 qRT-PCR 研究表明，雄激素可诱导雄激素依赖性前列腺癌细胞中 SSAT 基因的过度表达。我们的初步数据表明，用 APAO 抑制剂 MDL 预处理雄激素依赖性 LNCaP 细胞可以完全消除雄激素诱导的氧化应激。在这里，我们建议开发专门降低前列腺细胞氧化应激的 MDL，作为预防前列腺癌发生、生长和/或进展的药物。我们的具体目标是： 1) 通过二氯荧光 (DCF) 氧化测定，确定 MDL 预处理阻断雄激素依赖性前列腺癌细胞系 LapC4 和 LNCaP 中雄激素诱导的氧化应激的能力。 2)使用氢乙啶(HEt)氧化法测定MDL降低裸鼠模型中LNCaP肿瘤异种移植物氧化应激的能力。 3)确定MDL阻止裸鼠LNCaP和LapC4肿瘤异种移植物生长的能力。 4) 确定MDL在小鼠前列腺转基因腺癌​​（TRAMP）模型中预防自发性前列腺肿瘤形成的能力。这些目标的成功完成不仅将使 MDL 成为一种潜在的前列腺癌化学预防剂，可以进一步开发用于临床，而且还应证明多胺分解代谢途径作为前列腺癌化学预防的有效靶点的重要性。