MOLECULAR TARGETS OF ANTI-TUMOR NSAIDS

描述(由申请人提供)： 非类固醇抗炎药(NSAIDs)是可能用于预防和治疗癌症的有吸引力的候选药物。然而，它们的最终使用可能会与其他疗法结合使用。合理地开发化学预防或治疗的组合方法需要准确地了解由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受这些药物调控的新的分子靶点，促进抗肿瘤非类固醇抗炎药的开发，用于前列腺癌的化学预防。我们的研究将集中在R-氟比洛芬(R-FB)，一种芳基丙酸衍生物，在前列腺癌模型中显示出化学预防活性。我们已经使用基因表达谱来识别前列腺癌中受R-FB调节的基因。这些研究已经确定了CYP24 (=维生素D 24-羟基酶)作为一种基因被R-FB有效下调。因此，拟议的研究将寻求开发更多的数据来表征R-FB和CYP24调控过程之间的相互作用。我们将特别寻求1)通过使用标准的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细胞色素P24的调节和维生素D受体表达的影响。这些研究将确定可以与1，25(OH)2维生素D3一起作用于促进细胞色素P24表达的共刺激信号，并确定R-FB是否可以阻断这种信号通路。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的肿瘤和组织中的CYP24。此外，我们将使用体外和体内模型来表征R-FB和1，25(OH)2维生素D3的联合抗肿瘤作用，以阐明这些药物是否具有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等抗肿瘤非类固醇抗炎药和维生素D类似物结合起来，用于预防和治疗包括前列腺癌在内的恶性肿瘤。

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.