MOLECULAR TARGETS OF ANTI-TUMOR NSAIDS

抗肿瘤 NSAIDS 的分子靶点

• 批准号: 7391006
• 负责人: MICHAEL B LILLY
• 金额: $ 3.09万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-06 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7391006
• 关键词: antineoplastics; apoptosis; cell cycle; cell line; cell proliferation; cytokine; drug interactions; enzyme activity; epithelium; gene expression; genetic promoter element; immunocytochemistry; immunologic substance development /preparation; laboratory mouse; messenger RNA; neoplasm /cancer pharmacology; nonsteroidal antiinflammatory agent; oxygenases; pharmacokinetics; phorbols; prostate; receptor expression; recombinant proteins; testosterone; tissue /cell culture; vitamin D receptors

DESCRIPTION (provided by applicant): Non-steroidal anti-inflammatory drugs (NSAIDs) are attractive candidates for agents that may be useful for the prevention and treatment of cancers. However, their ultimate use will likely be in combination with other therapies. Rational development of combined approaches for chemoprevention or therapy requires an accurate knowledge of the molecular events regulated by the component drugs. The long-term goal of the proposed studies is to enhance the development of anti-tumor NSAIDs for chemoprevention of prostate cancer, by identifying and validating novel molecular targets regulated by these agents. Our studies will focus on R-flurbiprofen (R-FB), an arylpropionic acid derivative with demonstrated chemopreventive activity in prostate cancer models. We have used gene expression profiling to identify R-FB-regulated genes in prostate cancer. These studies have identified CYP24 (= vitamin D 24-hydroxylase) as a gene potently down-regulated by R-FB. The proposed studies will therefore seek to develop further data to characterize the interaction between R-FB and CYP24 regulatory processes. We will specifically seek to 1) characterize R-FB effects on CYP24 regulation and vitamin D receptor expression in prostate epithelial cell lines, through use of standard molecular and cell biology techniques. These studies will identify co-stimulatory signals that can act with 1,25(OH)2 vitamin D3 to promote CYP24 expression, and determine if R-FB can block such signal pathways. 2) We will develop antibodies to allow us to study CYP24 in intact tumors and tissues through immunohistochemistry. Furthermore we will 3) characterize the anti-tumor effects of R-FB in combination with 1,25(OH)2 vitamin D3 using in vitro and in vivo models, to clarify if there are additive or synergistic anti-proliferative effects from these agents. These studies will establish a basis for eventual clinical trials combining anti-tumor NSAIDs such as R-FB, and vitamin D analogues, for the prevention and treatment of malignancies, including prostate cancer.

描述（由申请人提供）： 非甾体抗炎药 (NSAID) 是可用于预防和治疗癌症的有吸引力的候选药物。然而，它们的最终用途可能是与其他疗法结合使用。合理开发化学预防或治疗的组合方法需要准确了解成分药物调节的分子事件。拟议研究的长期目标是通过识别和验证这些药物调节的新分子靶标，促进用于前列腺癌化学预防的抗肿瘤非甾体抗炎药的开发。我们的研究将集中于 R-氟比洛芬 (R-FB)，这是一种芳基丙酸衍生物，在前列腺癌模型中已证明具有化学预防活性。我们使用基因表达谱来识别前列腺癌中 R-FB 调节的基因。这些研究已确定 CYP24 （= 维生素 D 24-羟化酶）作为 R-FB 有效下调的基因。因此，拟议的研究将寻求开发进一步的数据来表征 R-FB 和 CYP24 调节过程之间的相互作用。我们将特别寻求 1) 通过使用标准分子和细胞生物学技术来表征 R-FB 对前列腺上皮细胞系中 CYP24 调节和维生素 D 受体表达的影响。这些研究将鉴定可与 1,25(OH)2 维生素 D3 共同作用促进 CYP24 表达的共刺激信号，并确定 R-FB 是否可以阻断此类信号通路。 2) 我们将开发抗体，使我们能够通过免疫组织化学研究完整肿瘤和组织中的 CYP24。此外，我们将 3) 使用体外和体内模型来表征 R-FB 与 1,25(OH)2 维生素 D3 组合的抗肿瘤作用，以阐明这些药物是否存在相加或协同的抗增殖作用。这些研究将为最终的临床试验奠定基础，将 R-FB 等抗肿瘤 NSAID 与维生素 D 类似物相结合，用于预防和治疗包括前列腺癌在内的恶性肿瘤。