BIOCHEMICAL STUDIES

这项研究计划的总体目标是建立一个合理的 癌症联合化疗的基础。 的 方法是基于采用以下组合的概念： 代谢物和抗代谢物，以调节生化 以实现最大的癌细胞损伤的途径 同时保护正常宿主细胞免受药物 毒性 许多基本信息， 对于一个特定的药物组合是基于来自体外 别人的研究。 然而，由于药物的最终效用 组合取决于选择性地实现 体内生物化学途径的适当调节，研究 在研究项目2中，将设计用于确定 给定的调节剂对最终的生物化学效应 主要效应剂在体内的活性。 因此，治疗 特定药物操作的结果，按预期获得 根据生化信息， 操纵，将在生化水平上得到证实，以确保 生物学结果与预测的 生化变化 意想不到的治疗效果将是 在生物化学水平上进行了探索， 将用于改变药物组合（或时间表）， 以实现所需的治疗进展。 (It必须强调 生物化学研究将在 获得自经历体内治疗方案的小鼠， 问题）。 非常重要的是，这些体内生物化学和 药理学研究将为比较 临床药理学和生物化学研究（研究 项目4，临床研究），将用于调整有希望的 用于从动物模型转化的治疗药物方案 to cancer癌症patients病人. 结合体内生物学和生物化学的发现，项目 1和2，导致特定临床试验的指南;反馈 来自项目4，临床研究，可能表明新的实验 研究和改进。

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.