TARGETING CERAMIDE METABOLISM FOR CANCER TREATMENT

描述(由申请人提供)： 此应用程序的长期目标是评估特定的 新抗癌药物发现和临床试验的分子靶点， 基于化疗耐药的分子机制。当前 抗癌药物作用机制及耐药生物学研究进展 发现神经酰胺糖基化是与血管紧张素转换酶进展相关的事件 癌症。这个应用的重点是靶向糖基化，因为它是 对维持耐药表型至关重要。据信， 一种新的药物类型可以被提出用于临床评估，基于 很有说服力。已知具有抗药性的人类癌细胞 证明神经酰胺通过糖基化途径代谢增强 由葡萄糖神经酰胺合成酶(GCS)催化，将暴露于常规 化疗，阿霉素，紫杉醇，N-4(羟基苯基)维甲酰胺(4-HPR) 没有或存在延缓神经酰胺糖基化的药物，后者 通过筛选天然产品中的化合物和 国家情报局的合成储存库。我们将对 使用已被证明可以延缓神经酰胺的先导化合物的储存库 糖基化，并显示与经典的协同细胞毒性 化疗药物。其他程序，如比较和集群 算法将被用来挖掘NCI的药库。网络的影响 神经酰胺糖基化的选择性药物将在完整的癌症中进行评估 细胞和体外无细胞分析，并根据结果，方案将是 单独或联合化疗进行细胞毒性评估， 采用标准的细胞增殖和凋亡检测方法。这项研究有两个 具体目标：1)筛选天然和合成NCI中的化合物 阻止神经酰胺代谢能力的产品储存库 糖基化路线；2)评价先导化合物的单独和组合 联合应用抗癌药物增强化疗诱导的细胞毒作用 耐药癌细胞。现有药物治疗的疗效有限 而化疗耐药的高发生率是追求的强大理由 治疗癌症患者的新方法。功能障碍性神经酰胺 新陈代谢是化疗和放射治疗失败的重要原因。 因此，靶向神经酰胺代谢是一种有吸引力的策略 抗癌药物开发。

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.