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: 7213330
• 负责人: Hirak S. Basu
• 金额: $ 7.14万
• 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/7213330
• 关键词: Ablation; Acetylation; Adenocarcinoma; Affect; Androgens; Animal Model; Animals; Antioxidants; Biological Assay; Butane; Butanes; Cancer Etiology; Cancer Patient; Cells; Cessation of life; Chemoprevention; Chemopreventive Agent; Clinical; DNA Microarray Chip; DNA Microarray format; Data; Development; Diagnosis; Diamines; Disease; Enzymes; Eukaryotic Cell; Free Radicals; Genes; Gland; Growth; Hormones; Hydrogen Peroxide; Hydroxyl Radical; LAPC4; LNCaP; Laboratories; Link; MDL-1 receptor; Malignant - descriptor; Malignant neoplasm of prostate; Mammals; Metabolic Pathway; Metabolism; Metastatic Prostate Cancer; Methods; Microarray Analysis; Modeling; Mus; Nitric Oxide; Normal tissue morphology; Nude Mice; Oxidative Stress; PC3 cell line; Pathway interactions; Personal Satisfaction; Play; Polyamine Catabolism; Polyamines; Preventive; Production; Prostate; Prostatic Neoplasms; Prostatic Tissue; Protein Overexpression; Putrescine; Radiosurgery; Reactive Oxygen Species; Refractory; Reporting; Role; Spermidine; Spermidine/Spermine N1-Acetyltransferase; Spermine; Superoxides; Time; Tissues; Transgenic Organisms; cancer cell; carcinogenesis; chemotherapeutic agent; disorder control; hydroethidine; inhibitor/antagonist; men; mouse model; novel; oxidation; polyamine oxidase; polycation; prevent; success; tumor; tumor xenograft

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。由于常用化疗药物在治疗前列腺癌方面的成功有限，迫切需要开发新型药物来预防其发生和进展。前列腺肿瘤组织中活性氧（ROS）如过氧化氢、超氧化物、羟自由基和一氧化氮水平相对高于正常组织。在过去的5年中，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。也已经证明雄激素调节雄激素依赖性前列腺癌细胞中的ROS产生。虽然ROS产生的确切机制仍然未知，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，然后通过产生ROS的乙酰多胺氧化酶（APAO）氧化而分解代谢。我们实验室最近进行的DNA微阵列分析和qRT-PCR研究表明，雄激素诱导雄激素依赖性前列腺癌细胞中SSAT基因的过表达。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细胞完全消除雄激素诱导的氧化应激。在这里，我们建议开发MDL，特异性地降低前列腺细胞中的氧化应激，作为可以预防前列腺癌的发生，生长和/或进展的药剂。我们的具体目标是：1）通过二氯荧光（dichlorofluorescene，DCF）氧化分析，建立MDL预处理阻断雄激素依赖性前列腺癌细胞系LapC 4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LNCaP肿瘤异种移植物中氧化应激的能力。3)确定MDL预防裸鼠中LNCaP和LapC 4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确立MDL作为潜在的前列腺癌化学预防剂，可以进一步开发用于临床使用，但也应该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。