BIOCHEMICAL STUDIES

生化研究

• 批准号: 3820263
• 负责人: DANIEL S MARTIN
• 金额: --
• 依托单位: ST. VINCENT CATHOLIC MEDICAL CTR NURSING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3820263
• 关键词: N phosphonoacetyl L aspartate; antimetabolites; antineoplastics; biochemistry; breast neoplasms; combination chemotherapy; cytidine; disease /disorder model; dosage; drug metabolism; drug screening /evaluation; enzyme inhibitors; enzyme mechanism; fluorouracil; high performance liquid chromatography; human tissue; laboratory mouse; methotrexate; neoplasm /cancer chemotherapy; nucleic acid inhibitor; pharmacokinetics; purine /pyrimidine metabolism; thymidylate synthase; uridine; uridine monophosphate

The overall goal of this research program is to establish a rational foundation for the combination chemotherapy of cancer. The approach is based on the concept of employing combinations of metabolites and antimetabolites to modulate biochemical pathways with the view of achieving maximal cancer cell damage while simultaneously protecting normal host cells from drug toxicity. Much of the basic information upon which a rationale for a particular drug combination is based comes from in vitro studies of others. However, since the ultimate utility of a drug combination depends upon the selective achievement of the appropriate modulation(s) of biochemical pathways in vivo, studies in Research Project 2 will be designed to determine the biochemical effect of a given modulating agent on the final activity of the primary effector agent in vivo. Thus, therapeutic results from a particular drug manipulation, obtained as expected on the basis of the biochemical information that prompted that manipulation, will be confirmed on a biochemical level to insure that the biological results are related to the predicted biochemical changes. Unexpected therapeutic results will be explored at the biochemical level to provide new information that will be utilized to alter the drug combination (or schedule) so as to achieve the desired therapeutic advance. (It must be stressed that the biochemical studies will be performed with tissues obtained from mice undergoing the in vivo therapeutic regimen in question). Of great importance, these in vivo biochemical and pharmacological studies will provide guidelines for comparative pharmacological and biochemical studies in the clinic (Research Project 4, Clinical Studies) which will be used to adjust promising therapeutic drug regimens for translations from the animal model to cancer patients. The combined in vivo biological and biochemical findings, Projects 1 and 2, lead to guidelines for specific clinical trails; feedback from Project 4, Clinical Studies, may suggest new experimental studies and refinements.

该研究计划的总体目标是建立一个理性的 癌症组合化疗的基础。 这 方法基于采用组合的概念 代谢物和抗代谢物可调节生化 具有实现最大癌细胞损害的途径 同时保护正常宿主细胞免受药物的影响 毒性。 基本原理的许多基本信息 对于特定的药物组合，基于体外 对他人的研究。 但是，由于药物的最终效用 组合取决于选择性成就 对体内生化途径的适当调节，研究 在研究项目2中将设计为确定 给定调节剂对最终的生化效应 体内主要效应剂的活性。 因此，治疗性 从预期获得的特定药物操纵的结果 基于生化信息，促使 操纵，将在生化水平上确认以确保 生物学结果与预测有关 生化变化。 意外的治疗结果将是 在生化一级探索，以提供新信息 将用于更改药物组合（或时间表），以便 为了实现所需的治疗进展。 （必须压力 将使用组织进行生化研究 从接受体内治疗方案的小鼠中获得 问题）。 非常重要的是，这些体内生化和 药理学研究将为比较提供指南 诊所的药理和生化研究（研究 项目4，临床研究）将用于调整有希望的 动物模型翻译的治疗药物方案 给癌症患者。 体内生物学和生化发现，项目 1和2，导致特定临床踪迹指南；反馈 从项目4中，临床研究可能提出新的实验 研究和改进。