COMBINATION THERAPY WITH BIOCHMICAL MODULATION AND MCA

拟议研究计划的最终目标是 开发更安全和更有效的组合 基于生物化学调节的癌症化疗。 药物 组合或药物-代谢物组合， 已知或潜在的生化相互作用的基础将是 用于操纵相关的生化途径， 治疗上有益的方式， 肿瘤细胞中的细胞毒性，和/或选择性地减少毒性 在正常的宿主细胞中。 此外，还提供了一种针对以下的单克隆抗体（MCA）： 小鼠乳腺肿瘤的表皮生长因子受体， 将被整合到一个综合治疗计划中， 生物化学选择的抗代谢物-代谢物组合。 其目标是增加的权力和选择性的 治疗性攻击，希望达到治愈晚期， 自发性实体癌，首先在小鼠模型中，然后 最终在患者中。 这种方法需要集成4个 项目：项目1，实验化疗;项目2， 生物化学研究;项目3，单克隆抗体研究;以及 项目4，临床研究。 临床前化疗研究 （项目1）将完全在体内鼠肿瘤中进行 模型 从一种特殊的药物操作中获得治疗效果， 根据生化信息， 这促使了微操纵，将在一个 生化水平（项目2），以确保生物学结果 与预测的生化变化有关。 意外 将在生化水平上探索治疗结果， 提供将用于改变药物的新信息 组合（或时间表）以实现期望的治疗效果 提前 体内生物化学和药理学研究 （项目2）在相同的动物肿瘤模型将提供 比较药理学和生物化学研究指南 在诊所（项目4），这将被用来调整有希望的 用于从动物肿瘤转化的治疗药物方案 癌症患者的模型。 结合体内生物学和 生化研究结果，项目1，2，导致具体的指导方针， 临床试验和临床研究的反馈可能表明， 新的实验研究和改进。

The ultimate goal of the proposed research program is the development of both safer and more effective combination chemotherapy for cancer based on biochemical modulation. Drug combinations, or drug-metabolite combinations, selected on the basis of known or potential biochemical interaction will be utilized to manipulate relevant biochemical pathways in a therapeutically beneficial manner to either potentiate selective cytotoxicity in tumor cells, and/or to selectively diminish toxicity in normal host cells. In addition, a monoclonal antibody (MCA) to the epidermal growth factor receptor of the murine breast tumor, will be integrated into a combined treatment plan with the biochemically selected antimetabolite-metabolite combinations. The goal is to increase both the power and selectively of the therapeutic attack, hopefully to the level of cure of advanced, spontaneous solid cancers, first in a murine model and then ultimately in patients. This approach requires the integration of 4 projects: Project 1, Experimental Chemotherapy; Project 2, Biochemical Studies; Project 3, Monoclonal Antibody Studies; and Project 4, Clinical Studies. Preclinical chemotherapy studies (Project 1) will be performed entirely in in vivo murine tumor models. Therapeutic results from a particular drug manipulation, obtained as expected on the basis of the biochemical information that prompted that minipulation, will be confirmed on a biochemical level (Project 2) 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. In vivo biochemical and pharmacological studies (Project 2) in the same animal tumor models will provide guidelines for comparative pharmacologic and biochemical studies in the clinic (project 4) which will be used to adjust promising therapeutic drug regimens for translation from the animal tumor model to cancer patients. The combined in vivo biological and biochemical findings, Projects 1, 2, lead to guidelines for specific clinical trials, and feedback from the clinical studies may suggest new experimental studies and refinements.