COMBINATION THERAPY WITH BIOCHEMICAL MODULATION AND MCA

拟议的研究计划的最终目标是 开发更安全和更有效的组合 基于生化调节的癌症化疗。药效 组合，或药物-代谢物组合，在 已知或潜在的生化相互作用的基础将是 用来操纵相关的生化途径 对治疗有益的方式来增强选择性 对肿瘤细胞的细胞毒性，和/或选择性地降低毒性 在正常宿主细胞中。此外，一种抗人免疫球蛋白的单抗 小鼠乳腺肿瘤的表皮生长因子受体， 将与联合治疗计划整合为 生物化学选择的抗代谢物-代谢物组合。 目标是增加权力和选择性地 治疗性发作，有望达到晚期， 自发性实体癌，先是小鼠模型，然后是 最终在病人身上。此方法需要集成4个 项目：项目1，实验性化疗；项目2， 生物化学研究；项目3，单抗研究；以及 项目4，临床研究。临床前化疗研究 (项目1)将完全在体内进行小鼠肿瘤 模特们。一种特殊药物操作的治疗结果， 在生化信息的基础上如期获得 这促使了微调，将在一次 生化水平(项目2)，以确保生物结果 与预测的生化变化有关。始料未及 治疗结果将在生化水平上进行探索，以 提供将被用来改变药物的新信息 联合(或计划)以达到所需的治疗效果 前进。体内生化和药理研究 (项目2)在相同的动物肿瘤模型中将提供 比较药理学和生化研究指南 在临床(方案4)中，将用于调整前景 从动物肿瘤转译的治疗药物方案 癌症患者的模特。体内生物学与生物医学相结合 生化发现，项目1，2，导致特定的指导方针 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.