MOLECULAR TARGETS OF ANTI-TUMOR NSAIDS

描述（由申请人提供）： 非甾体抗炎药（NSAID）是一种有吸引力的候选药物，可用于预防和治疗癌症。然而，它们的最终用途可能是与其他疗法联合使用。合理开发化学预防或治疗的联合方法需要准确了解组分药物调节的分子事件。拟议研究的长期目标是通过鉴定和验证受这些药物调节的新型分子靶点，加强抗肿瘤NSAID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，在前列腺癌模型中具有化学预防活性。我们已经使用基因表达谱来识别前列腺癌中的R-FB调节基因。这些研究已经确定了CYP 24 （=维生素D 24-羟化酶）作为一个基因有效下调R-FB。因此，拟定的研究将寻求开发进一步的数据，以表征R-FB和CYP 24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，表征R-FB对前列腺上皮细胞系中CYP 24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共同作用以促进CYP 24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CYP 24。此外，我们将3）使用体外和体内模型表征R-FB与1，25（OH）2维生素D3组合的抗肿瘤作用，以澄清这些药剂是否具有相加或协同抗增殖作用。这些研究将为联合抗肿瘤NSAID（如R-FB）和维生素D类似物预防和治疗恶性肿瘤（包括前列腺癌）的最终临床试验奠定基础。

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.