TARGETING CERAMIDE METABOLISM FOR CANCER TREATMENT

针对神经酰胺代谢进行癌症治疗

• 批准号: 6466112
• 负责人: Myles C. Cabot
• 金额: $ 18.88万
• 依托单位: SAINT JOHN'S CANCER INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6466112
• 关键词: antimetabolites; antineoplastics; breast neoplasms; ceramides; doxorubicin; drug interactions; drug resistance; drug screening /evaluation; fenretinide; glycosylation; lipid metabolism; neoplasm /cancer pharmacology; paclitaxel; tissue /cell culture

DESCRIPTION (provided by applicant): The long-term objective of this application is to evaluate a specific molecular target for discovery and clinical testing of new anticancer agents, based on molecular mechanisms that underlie chemotherapy resistance. Current research in anticancer drug mechanism of action and resistance biology has identified ceramide glycosylation as an event associated with progression of cancer. The focus of this application is to target glycosylation because it is essential for maintenance of the drug-resistant phenotype. It is believed that a new genre of agents can be brought forth for clinical assessment based on strong rationales. Drug-resistant human cancer cells which are known to demonstrate enhanced metabolism of ceramide through the glycosylation pathway catalyzed by glucosylceramide synthase (GCS), will be exposed to conventional chemotherapy, Adriamycin, Taxol, N-4(hydroxyphenyl)retinamide(4-HPR) in the absence or presence of agents that retard ceramide glycosylation, the latter being evaluated through screening of compounds in the Natural Products and Synthetic Repositories of the NCI. We will conduct analog searches of the repositories using lead compounds already shown to retard ceramide glycosylation and demonstrate synergistic cytotoxicity with classical chemotherapeutic agents. Other programs such as COMPARE and clustering algorithms will be employed to mine the NCI drug repositories. The impact of select agents on ceramide glycosylation will be evaluated in intact cancer cells and in in vitro cell-free assays, and based on results, regimens will be assessed for cytotoxicity either alone or in combination with chemotherapy, using standard cell proliferation and apoptosis assays. This study has two specific aims: 1) to screen compounds in the NCI Natural and Synthetic Products Repositories for ability to block ceramide metabolism by the glycosylation route; 2) to evaluate lead compounds alone and in combination with anticancer drugs for enhancement of chemotherapy-induced cytotoxicity in drug-resistant cancer cells. The limited efficacy of available drug therapies and the high incidence of chemotherapy resistance are strong reasons to pursue new approaches to treat patients with cancer. Dysfunctional ceramide metabolism is a significant contributor to chemo- and radiotherapy failure. Targeting ceramide metabolism is therefore an attractive strategy for anticancer drug development.

描述（由申请人提供）： 该应用程序的长期目标是评估特定的 新抗癌药物的发现和临床测试的分子靶标， 基于化疗耐药性的分子机制。当前的 抗癌药物作用机制及耐药生物学研究 确定神经酰胺糖基化是与进展相关的事件 癌症。该应用的重点是靶向糖基化，因为它是 对于维持耐药表型至关重要。据信 可以提出一种新的药物类型用于临床评估 强有力的理由。已知具有耐药性的人类癌细胞 证明通过糖基化途径增强神经酰胺的代谢 由葡萄糖神经酰胺合酶（GCS）催化，将暴露于常规 化疗、阿霉素、紫杉醇、N-4(羟苯基)视黄酰胺(4-HPR) 不存在或存在阻碍神经酰胺糖基化的药物，后者 通过筛选天然产物中的化合物进行评估 NCI 综合存储库。我们将进行模拟搜索 使用已被证明可以延迟神经酰胺的先导化合物的存储库 糖基化并证明与经典的协同细胞毒性 化疗剂。其他程序，例如 COMPARE 和聚类 将采用算法来挖掘 NCI 药物存储库。的影响 将在完整癌症中评估神经酰胺糖基化的选定药物 细胞和体外无细胞测定，并根据结果，将制定治疗方案 单独或与化疗联合评估细胞毒性， 使用标准细胞增殖和凋亡测定。这项研究有两个 具体目标：1) 筛选 NCI 天然和合成化合物 产品储存库能够通过以下方式阻断神经酰胺代谢： 糖基化途径； 2) 单独和组合评估先导化合物 与抗癌药物一起增强化疗诱导的细胞毒性 耐药癌细胞。现有药物疗法的疗效有限 化疗耐药的高发生率是追求的强有力理由 治疗癌症患者的新方法。功能失调的神经酰胺 新陈代谢是化疗和放疗失败的一个重要因素。 因此，针对神经酰胺代谢是一种有吸引力的策略 抗癌药物开发。