Exploratory Trial of Curcumin in Pancreatic Cancer

姜黄素治疗胰腺癌的探索性试验

• 批准号: 6930389
• 负责人: RAZELLE KURZROCK
• 金额: $ 20.39万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6930389
• 关键词: alternative medicine; antineoplastics; clinical research; clinical trials; enzyme activity; enzyme inhibitors; human subject; human therapy evaluation; interleukin 8; medicinal plants; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; neoplastic process; nuclear factor kappa beta; pancreas neoplasms; patient oriented research; pharmacokinetics; plant extracts; prostaglandin E; prostaglandin endoperoxide synthase

DESCRIPTION (provided by applicant): Pancreatic cancer is an almost uniformly fatal illness, which is notoriously resistant to conventional chemotherapy. Indeed, the only chemotherapeutic agent approved by the FDA for use in this tumor -- gemcitabine -- has a response rate of approximately 5%, underscoring the need for innovative new approaches. Curcumin (diferuloyl methane) is a plant-derived compound that has been used extensively as a dietary ingredient. In vitro and animal model studies suggest that this compound has significant antitumor and chemotpreventive activity. In addition, pharmacologic doses of curcumin have been administered to patients in the phase I setting without significant side effects. Recently, we have demonstrated that curcumin has potent antiproliferative effects against all of five pancreatic cancer cell lines, with the 50% inhibitory concentration (IC/50) being < 5 mu/M in three of these lines. The antiproliferative effects were irreversible, and substantial apoptosis was noted. Of interest, NF-KappaB, which is constitutively active in pancreatic cancer cell lines, was downregulated after curcumin exposure. Levels of effectors including COX-2 and IL-8 were also decreased. On the basis of these results, we propose to do an exploratory clinical/translational trial of curcumin in patients with pancreatic cancer. Our primary objectives will include clinical goals such as determining the tolerance to, as well as response to, curcumin in patients with advanced pancreatic cancer. In addition, the biologic effect of curcumin on both tumor cells and peripheral blood mononuclear cells (the latter being used as a surrogate marker) will be assessed. In particular, the impact of curcumin on NF-KappaB activation, COX-2 and prostaglandin E2 levels, specific cytokine expression, and apoptosis will be evaluated. These studies should provide the foundation for the development of curcumin as an anticancer agent and may lead to a novel approach to the management of pancreatic cancer.

描述（由申请人提供）：胰腺癌几乎是一种致命的疾病，众所周知，它对传统化疗具有抵抗力。事实上，FDA 批准用于治疗这种肿瘤的唯一化疗药物——吉西他滨——的缓解率约为 5%，这凸显了对创新方法的需求。姜黄素（二阿魏酰甲烷）是一种植物源性化合物，已广泛用作膳食成分。体外和动物模型研究表明该化合物具有显着的抗肿瘤和化学预防活性。此外，药物剂量的姜黄素已在第一阶段的治疗中给予患者，没有出现明显的副作用。最近，我们证明姜黄素对所有五种胰腺癌细胞系均具有有效的抗增殖作用，其中三种细胞系的 50% 抑制浓度 (IC/50) < 5 mu/M。抗增殖作用是不可逆的，并且注意到大量的细胞凋亡。有趣的是，在胰腺癌细胞系中具有持续活性的 NF-KappaB 在接触姜黄素后表达下调。包括 COX-2 和 IL-8 在内的效应物水平也有所下降。根据这些结果，我们建议对胰腺癌患者进行姜黄素的探索性临床/转化试验。我们的主要目标包括临床目标，例如确定晚期胰腺癌患者对姜黄素的耐受性和反应。此外，还将评估姜黄素对肿瘤细胞和外周血单核细胞（后者用作替代标记物）的生物效应。特别是，将评估姜黄素对 NF-KappaB 激活、COX-2 和前列腺素 E2 水平、特定细胞因子表达和细胞凋亡的影响。这些研究应该为姜黄素作为抗癌药物的开发奠定基础，并可能带来一种治疗胰腺癌的新方法。