Identification of a Molecular Target for the Anti Tumor

抗肿瘤分子靶标的鉴定

• 批准号: 6515087
• 负责人: Barry M. Forman
• 金额: $ 17.5万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-12 至 2004-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6515087
• 关键词: P glycoprotein; analog; antineoplastics; antisense nucleic acid; cell line; chemical structure function; drug screening /evaluation; high throughput technology; method development; multidrug resistance; neoplasm /cancer pharmacology; neoplastic cell; northern blottings; nuclear receptors; oligonucleotides; polymerase chain reaction; receptor expression

DESCRIPTION: (provided by applicant) Ecteinascidin-743 (ET-743) is a novel, low molecular weight, anti-neoplastic drug which possesses extremely potent cytotoxicity against human cancer cell lines and human xenografts. The drug is particularly useful against a variety of sarcomas which generally lack alternative chemotherapeutic options. Phase I studies have demonstrated objective responses and phase II studies are currently underway. Despite the promise that this drug offers, its molecular target remains to be elucidated. ET-743 is known to decrease the rate of transcription of the MDRl (P- glycoprotein) gene. The data presented here indicate that the orphan nuclear receptor SXR can activate transcription of the MDRl. This led us to test whether the transcriptional inhibitory effects of ET-743 may be mediated be SXR. Indeed, ET-743 inhibits transactivation of SXR (IC50 = 5 nM) at the same concentrations that it acts as an antitumor agent. These data suggest that SXR is a molecular target for ET-743 and further imply that SXR, a modulator of MDRl, is a potential target for anti-tumor therapies. ET-743 is a tetrahydroisoquinoline alkaloid isolated from the marine tunicate Ecteinascidia turbinata and has been difficult to purify or synthesize in bulk quantities. The identification of a nuclear receptor as a molecular target for ET-743 would provide a rapid, high-throughput assay for the screening of alternative synthetic or natural product inhibitors. We propose to further validate the role of SXR as an anti-tumor target, to delineate the mechanism by which ET-743 inhibits SXR, and to develop assays that can later be utilized for high-throughput screening of low molecular weight chemical libraries.

描述：（申请人提供） Ecteinascidin-743（ET-743）是一种新型的低分子量，抗塑性塑料 对人类癌细胞具有极有效的细胞毒性的药物 线和人异种移植物。该药物特别有用 通常缺乏替代化学治疗选择的肉瘤。第一阶段 研究表明客观反应和第二阶段研究是 目前正在进行中。尽管有这种药物提供的承诺，但其分子 目标仍有待阐明。 已知ET-743会降低MDRL的转录速率（P- 糖蛋白）基因。这里提供的数据表明孤儿核 受体SXR可以激活MDRL的转录。这使我们进行了测试 ET-743的转录抑制作用是否可以介导 sxr。实际上，ET-743抑制SXR（IC50 = 5 nm）的反式激活 它充当抗肿瘤剂的浓度。这些数据表明SXR 是ET-743的分子靶标，进一步暗示SXR，一个调节剂 MDRL是抗肿瘤疗法的潜在靶标。 ET-743是一种从海洋调皮分离的四氢异喹啉生物碱 Ecteinascidia turbinata，很难净化或合成 数量。将核受体鉴定为一个分子靶标 ET-743将为筛选提供快速，高通量的测定 替代合成或天然产物抑制剂。我们建议进一步 验证SXR作为抗肿瘤目标的作用，以描绘机制 ET-743抑制SXR，并开发可用于使用的测定 用于低分子量化学文库的高通量筛选。