Exploratory Trial of Curcumin in Pancreatic Cancer

描述（由申请人提供）：胰腺癌是一种几乎一致致命的疾病，众所周知，它对常规化疗具有抵抗力。事实上，FDA批准用于这种肿瘤的唯一化疗药物-吉西他滨-的反应率约为5%，强调了对创新新方法的需求。姜黄素（二阿魏酰甲烷）是一种植物衍生的化合物，已被广泛用作膳食成分。体外和动物模型研究表明，该化合物具有显著的抗肿瘤和化学预防活性。此外，药理学剂量的姜黄素已在I期环境中施用于患者，而没有显著的副作用。最近，我们已经证明姜黄素对所有五种胰腺癌细胞系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 μ/M。抗增殖作用是不可逆的，并注意到大量的细胞凋亡。有趣的是，在胰腺癌细胞系中具有组成性活性的NF-κ B在姜黄素暴露后下调。效应物包括考克斯-2和IL-8的水平也降低。在这些结果的基础上，我们建议在胰腺癌患者中进行姜黄素的探索性临床/转化试验。我们的主要目标将包括临床目标，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（后者用作替代标志物）的生物学效应。具体而言，将评价姜黄素对NF-κ B活化、考克斯-2和前列腺素E2水平、特异性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发展提供基础，并可能导致胰腺癌管理的新方法。

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.