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

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。在临床上显著的前列腺癌的发展中涉及的长潜伏期提供了使用化疗或饮食化合物成功预防或延迟这种致命疾病的机会，并且是降低发病率和死亡率的有希望的方法。在我们实验室中进行的初步研究发现，丁香酚（丁香中发现的香料）和低剂量的2-甲氧基乙烯（2-ME 2）的组合显著增强了前列腺癌细胞的增殖抑制并诱导了细胞凋亡（美国专利#6518261B2）。文献中未报告评估联合用药疗效的研究。为响应PAR-08-055而提交的该中试申请的目的是确定在采取详细和详细的作用机制之前，体外观察结果是否可以在体内重现。因此，在该试验性应用中，我们假设“2-ME 2加丁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将比任一单一药剂更有效”。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进行测试。通过（i）进展期间的非侵入性氟-18氟脱氧葡萄糖（FDG）-PET和（ii）实验结束时的前列腺组织学评价监测肿瘤发展的抑制。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。拟议的研究将提供关于联合药物与各单药在体内相比的有效性的“原理数据证明”。这些数据对于开发这种用于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（R 01），以（i）确定联合用药最有效的阶段;（ii）研究该联合用药的作用机制;（iii）使用遗传和分子方法验证所确定的靶点，以预防、逆转或抑制癌前病变的进展。

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.