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：（由申请人提供） Ecteinascidin-743 (ET-743) 是一种新型低分子量抗肿瘤药物 对人类癌细胞具有极强细胞毒性的药物 系和人类异种移植物。该药物特别适用于对抗多种 通常缺乏替代化疗方案的肉瘤。第一阶段 研究已经证明了客观的反应，并且 II 期研究正在 目前正在进行中。尽管这种药物提供了希望，但它的分子 目标仍有待明确。 已知 ET-743 会降低 MDR1 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MDR1的转录。这导致我们测试 ET-743 的转录抑制作用是否可能是通过介导的 SXR。事实上，ET-743 同时抑制 SXR 的反式激活 (IC50 = 5 nM) 其作为抗肿瘤剂的浓度。这些数据表明 SXR 是 ET-743 的分子靶点，进一步表明 SXR 是一种调节剂 MDR1是抗肿瘤治疗的潜在靶标。 ET-743 是一种从海洋被囊动物中分离出来的四氢异喹啉生物碱 Ecteinascidia turbinata 很难大量纯化或合成 数量。鉴定核受体作为分子靶标 ET-743 将为筛选提供快速、高通量的检测方法 替代合成或天然产物抑制剂。我们建议进一步 验证 SXR 作为抗肿瘤靶点的作用，阐明其机制 ET-743 通过其抑制 SXR，并开发可供以后使用的检测方法 用于低分子量化学文库的高通量筛选。