Prostate-Directed Antioxidant to Prevent Prostate Cancer

前列腺定向抗氧化剂可预防前列腺癌

基本信息

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
项目类别：
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

项目摘要

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。由于常用的化学治疗剂在治疗前列腺癌方面的成功有限，因此迫切需要开发新型药物以防止其发生和进展。活性氧（ROS），例如过氧化氢，超氧化物，羟基自由基和一氧化氮水平在前列腺肿瘤中的水平相对较高。在过去的五年中，已有报道称ROS与各种组织中肿瘤发展的增加有关，包括前列腺中的肿瘤发展。还证明，雄激素调节依赖性前列腺癌细胞中的ROS产生。尽管ROS产生的确切机制尚不清楚，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了大量的多胺。多胺通过精子/精子乙酰转移酶（SSAT）通过乙酰化分解代谢，然后通过产生ROS的乙酰聚胺氧化酶（APAO）氧化。最近在我们的实验室中进行的DNA微阵列分析和QRT-PCR研究表明，雄激素在依赖雄激素依赖的前列腺癌细胞中诱导SSAT基因过表达。我们的初步数据表明，使用APAO抑制剂MDL对雄激素依赖性LNCAP细胞进行预处理，完全消除了雄激素诱导的氧化应激。在这里，我们建议开发MDL，以专门降低前列腺细胞中的氧化应激，作为一种可以防止前列腺癌的发生，生长和/或进展的药物。我们的具体目的是：1）建立MDL预处理阻止雄激素诱导的氧化应激在依赖性前列腺癌细胞系LAPC4和通过二氯氟氟乙烯（DCF）氧化测定的能力。 2）确定使用氢乙胺（HET）氧化方法在裸小鼠模型中降低LNCAP肿瘤异种移植中氧化应激的能力。 3）确定MDL防止LNCAP和LAPC4肿瘤异种移植物在裸小鼠中的能力。 4）确定MDL预防小鼠前列腺（Tramp）模型中转基因腺癌中自发前列腺肿瘤形成的能力。这些目标的成功完成不仅将建立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，而且还应证明多胺分解代谢途径是前列腺癌化学预防的有效靶标。