Eugenol & 2-methoxyestradiol: combination approach to prostate cancer prevention

丁子香酚

• 批准号: 7752402
• 负责人: ADDANKI PRATAP KUMAR
• 金额: $ 7.42万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7752402
• 关键词: 2-methoxyestradiol; Acquired Immunodeficiency Syndrome; Address; Adenocarcinoma; Aging; Animals; Antineoplastic Agents; Apoptosis; Apoptotic; Biological; Biological Availability; Cancer Etiology; Carcinoma; Cessation of life; Cinnamon - dietary; Clinical; Clove; Data; Development; Disease; Dose; Drug resistance; Eugenol; Evaluation; Flavoring; Fluorine; Goals; Growth; Half-Life; Human; Immunohistochemistry; In Vitro; Laboratories; Left; Legal patent; Lesion; Literature; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metabolic; Molecular Genetics; Monitor; Morbidity - disease rate; Mus; Oils; Phenols; Play; Premalignant; Prevention; Probability; Prostate; Prostatic Neoplasms; Publishing; Quality of life; Relative (related person); Reporting; Research Project Grants; Resistance; Resources; Role; Signal Pathway; Signaling Molecule; Spices; Staging; Testing; Tissue Sample; Toxic effect; Transgenic Organisms; Tuberculosis; Tumor Suppression; Volatile Oils; base; cancer cell; clinically significant; combat; combinatorial; fluorodeoxyglucose; fluorodeoxyglucose positron emission tomography; hormone refractory prostate cancer; human disease; improved; in vivo; innovation; leukemia; male; mortality; mouse model; novel; prevent; prostate cancer prevention; research study; response; synergism; tumor

DESCRIPTION (provided by applicant): Prostate cancer (PCA) is the second leading cause of cancer related deaths in aging males. The long-latency involved in the development of clinically significant prostate cancer, provides opportunities for successfully prevention or delay of this fatal disease using chemo or dietary compounds and is a promising approach to reduce morbidity and mortality. Preliminary studies conducted in our laboratory led to the discovery that a combination of eugenol (a spice found in cloves) and low dose of 2-methoxyestradiol (2-ME2) significantly enhanced proliferation inhibition and induced apoptosis in prostate cancer cells (US Patent #6518261B2). No studies to assess the efficacy of the combination have been reported in the literature. The goal of this pilot application submitted in response to PAR-08-055 is to determine whether the in vitro observations can be recapitulated in vivo before elaborate and detailed mechanism of action is taken up. Accordingly in this pilot application we hypothesize that "combination of 2-ME2 plus eugenol will be more effective than either single agent in preventing the development of well differentiated cancer by modulating apoptosis". This hypothesis will be tested in a mouse model of prostate cancer with high relevance to human disease. Suppression of tumor development will be monitored by (i) non-invasive Fluorine-18 fluorodeoxyglucose (FDG)-PET during progression and (ii) histological evaluation of the prostate at the termination of the experiment. Expression of apoptotic signaling molecules will be analyzed in the tissue samples using immunohistochemistry. The proposed studies will provide "proof of principle data" regarding the usefulness of the combined agents compared with each single agent in vivo. These data are essential for developing this combination for prostate cancer prevention in humans. In addition these studies will generate sufficient preliminary data that will facilitate submitting more detailed and expanded research project (R01) to (i) define the stage where the combination would be most effective; (ii) investigate the mechanism of action of this combination; and (iii) validate the identified target(s) to prevent, reverse or inhibit progression of precancerous lesions using genetic and molecular approaches.

描述（由申请人提供）： 前列腺癌（PCA）是老年男性癌症相关死亡的第二大原因。具有临床意义的前列腺癌的发展具有较长的潜伏期，为使用化疗或饮食化合物成功预防或延迟这种致命疾病提供了机会，并且是降低发病率和死亡率的有前途的方法。我们实验室进行的初步研究发现，丁香酚（丁香中的一种香料）和低剂量 2-甲氧基雌二醇 (2-ME2) 的组合可显着增强前列腺癌细胞的增殖抑制并诱导细胞凋亡（美国专利#6518261B2）。文献中尚未报道评估联合用药疗效的研究。针对 PAR-08-055 提交的试点申请的目的是确定在详细阐述作用机制之前是否可以在体内重现体外观察结果。因此，在该试点应用中，我们假设“2-ME2 加丁子香酚的组合在通过调节细胞凋亡来预防分化良好的癌症的发展方面比任一单一药物更有效”。这一假设将在与人类疾病高度相关的前列腺癌小鼠模型中得到检验。肿瘤发展的抑制将通过(i)进展期间的非侵入性氟18氟脱氧葡萄糖(FDG)-PET和(ii)实验结束时前列腺的组织学评估来监测。将使用免疫组织化学分析组织样品中凋亡信号分子的表达。拟议的研究将提供有关组合药物与体内每种单一药物相比的有效性的“原理数据证明”。这些数据对于开发这种预防人类前列腺癌的组合至关重要。此外，这些研究将产生足够的初步数据，有助于提交更详细和扩展的研究项目（R01），以（i）确定组合最有效的阶段； (ii) 研究该组合的作用机制； (iii) 使用遗传和分子方法验证已确定的目标，以预防、逆转或抑制癌前病变的进展。