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的目标是开发一种基于以下内容的癌症治疗策略： E. coliPNP在肿瘤细胞中的表达。的一个主要 在这个NCDDG生物化学计划的目标是充分 嘌呤核苷类似物的生化药理学特征 可以用作前药。此程序将与 化学和X射线晶体学程序的合理设计 嘌呤核苷类似物可被E.杆菌 菲律宾国家警察在这些研究中，利用各种前药的E。杆菌 PNP和可能代谢嘌呤核苷的人体酶 将测定前药在整个动物中的代谢， 将表征细胞培养物。 这些研究对于 确定负责产生有毒代谢物的主要酶 前药。这些信息将有助于合理开发更少的 仍然可以被E. coli PNP。另一个主要 本程序的目的是确定E.大肠杆菌PNP 在分子生物学中将要开发的各种肿瘤模型， 程序，并充分表征前药与 这些肿瘤。这些信息对于充分解释 测量各种前药功效的实验结果 针对表达E. coli PNP。此外， E.大肠杆菌PNP 我们对此知之甚少，这将是本计划的目标之一， 来确定它们的作用机制，这样我们就可以了解它们是如何 不同于传统疗法。这些研究将共同支持 NCDDG的目标，通过提供生物化学信息， 必要的合理发展这一战略的治疗 癌症。