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，它对传统化疗具有耐药性。事实上，FDA批准的唯一用于该肿瘤的化疗药物吉西他滨（gemcitabine）的缓解率约为5%，这表明需要创新的新方法。姜黄素（异丙基甲烷）是一种植物衍生化合物，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，姜黄素的药理学剂量已被用于I期患者，没有明显的副作用。最近，我们已经证明姜黄素对所有五种胰腺癌细胞系都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。其抗增殖作用是不可逆的，并引起大量细胞凋亡。有趣的是，在胰腺癌细胞系中具有组成性活性的NF-KappaB在姜黄素暴露后被下调。包括COX-2和IL-8在内的效应物水平也有所下降。基于这些结果，我们建议在胰腺癌患者中开展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，姜黄素对肿瘤细胞和外周血单个核细胞（后者被用作替代标记物）的生物学效应将被评估。特别是，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将被评估。这些研究将为姜黄素作为抗癌药物的开发提供基础，并可能为胰腺癌的治疗提供新的途径。

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.