BIOCHEMISTRY OF PURINE NUCLEOSIDE ANALOGS ACTIVATED BY E COLI PNP

大肠杆菌 PNP 激活的嘌呤核苷类似物的生物化学

• 批准号: 6203306
• 负责人: WILLIAM B PARKER
• 金额: $ 13.51万
• 依托单位: SOUTHERN RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6203306
• 关键词: Escherichia coli; antineoplastics; cerebrospinal fluid; cooperative study; cytotoxicity; deoxyadenosines; drug metabolism; enzyme activity; enzyme mechanism; enzyme substrate; high performance liquid chromatography; laboratory mouse; neoplasm /cancer pharmacology; neoplastic cell; phosphorylation; prodrugs; purine analog; purine nucleoside phosphorylase; purine nucleosides; tissue /cell culture

The goal of this NCDDG is to develop a cancer treatment strategy based on the selective expression of E. coli PNP in tumor cells. One of the major objectives of the Biochemistry Program in this NCDDG is to fully characterize the biochemical pharmacology of purine nucleoside analogs that can be used as prodrugs. This program will interact with the Chemistry and X-ray Crystallography Programs in the rational design of purine nucleoside analogs that can be selectively activated by E. coli PNP. In these studies the utilization of the various prodrugs by E. coli PNP and human enzymes that are likely to metabolize purine nucleosides will be determined, and the metabolism of prodrug in whole animals and cell culture will be characterized. These studies are necessary to identify the primary enzyme responsible for creating toxic metabolites of the prodrug. This information will aid in the rational development of less toxic prodrugs that can still be cleaved by E. coli PNP. Another major objective of this program is to determine the activity of E. coli PNP in the various tumor models that will be developed in the Molecular Biology Program and to fully characterize the interaction of the prodrugs with these tumors. This information is necessary to adequately interpret the results of the experiments that measure the efficacy of various prodrugs against tumors that express E. coli PNP. In addition, the mechanisms of action of many of the toxic purines that will be produced by E. coli PNP are poorly understood, and it will be the one of the goals of this program to determine their mechanisms of action so that we may understand how they differ from conventional therapy. Together these studies will support the goals of the NCDDG by supplying the biochemical information that is necessary for the rational development of this strategy for the treatment of cancer.

该 NCDDG 的目标是制定基于以下基础的癌症治疗策略： 大肠杆菌 PNP 在肿瘤细胞中的选择性表达。主要之一 本 NCDDG 中生物化学计划的目标是充分 表征嘌呤核苷类似物的生化药理学 可以用作前药。该程序将与 化学和X射线晶体学程序的合理设计 可以被大肠杆菌选择性激活的嘌呤核苷类似物 国民党。在这些研究中，大肠杆菌对各种前药的利用 PNP 和可能代谢嘌呤核苷的人类酶 将确定前体药物在整个动物和 将表征细胞培养物。 这些研究是必要的 确定负责产生有毒代谢物的主要酶 前体药物。这些信息将有助于更少的合理发展 仍可被大肠杆菌 PNP 裂解的有毒前药。另一个专业 该计划的目的是确定大肠杆菌 PNP 的活性 分子生物学将开发的各种肿瘤模型 规划并充分表征前药与 这些肿瘤。该信息对于充分解释 测量各种前药功效的实验结果 对抗表达大肠杆菌 PNP 的肿瘤。此外，机制 大肠杆菌 PNP 产生的许多有毒嘌呤的作用 知之甚少，这将是该计划的目标之一 确定它们的作用机制，以便我们了解它们如何 与传统疗法不同。这些研究将共同​​支持 NCDDG 的目标是通过提供生化信息 合理制定治疗策略所必需的 癌症。