TARGETING CERAMIDE METABOLISM FOR CANCER TREATMENT

描述（由申请人提供）： 本申请的长期目标是评估特定的 用于发现和临床测试新抗癌剂的分子靶标， 基于化疗耐药性的分子机制。电流 抗癌药物作用机制和耐药生物学的研究 确定神经酰胺糖基化为与以下疾病进展相关的事件： 癌本申请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 一种新类型的药物可以用于临床评估， 强有力的理由。耐药的人类癌细胞， 证明通过糖基化途径的神经酰胺代谢增强 由葡糖神经酰胺合酶（GCS）催化，将暴露于常规的 化疗，阿霉素，紫杉醇，N-4（羟苯基）维A酰胺（4-HPR） 不存在或存在阻滞神经酰胺糖基化的试剂，后者 通过筛选天然产品中的化合物进行评估， 国家癌症研究所的合成储存库。我们将进行模拟搜索 使用铅化合物的储存库已经显示出阻滞神经酰胺 糖基化，并证明与经典的 化疗剂。其他程序，如COMPARE和集群 算法将被用来挖掘NCI药物库。的影响 选择神经酰胺糖基化的药物将在完整的癌症中进行评估 细胞和体外无细胞试验，并根据结果，方案将 评估单独或与化疗联合的细胞毒性， 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天然和合成中的化合物 产品用于阻断神经酰胺代谢能力的储存库 糖基化途径; 2）评价单独和组合的先导化合物 与抗癌药物联合用于增强化疗诱导的细胞毒性， 抗药性癌细胞现有药物治疗的疗效有限 和化疗耐药的高发生率是追求的有力理由 治疗癌症患者的新方法。功能障碍性神经酰胺 代谢是化疗和放疗失败的重要原因。 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.