CANCER THERAPY WITH BIOCHEMICAL MODULATORS AND CSFS

拟议的研究计划的最终目标是开发 对癌症既安全又有效的联合疗法。基于 生化调节原理，药物组合，或药物- 代谢物组合，根据已知的或潜在的选择 生化交互作用，将被用来操纵相关 以一种对治疗有益的方式对 增强肿瘤细胞的选择性细胞毒性，和/或选择性地 降低对正常宿主细胞的毒性。严肃的寄主的控制 毒性被认为是实现化疗的关键 治愈，因为由此产生的药物选择性的操作增加将 允许数量和质量的强化 化疗。除了具体的“救援”方法之外 抗代谢毒性与相应的正常代谢物， 将尝试通过刺激来预防药物引起的毒性 在药物治疗疗程之间更快地恢复造血功能 造血生长因子；还有，具有潜在治疗作用的选定药物 节制，还是为了刺激药物损伤的更快恢复 将对肠上皮进行评估。目标是增加这两个方面 治疗性攻击的力量和选择性，希望对 晚期自发性实体癌的治愈水平，首次在小鼠身上进行 模型，然后最终在患者身上。此方法需要 3个项目的整合：项目1，实验治疗；项目2， 生化研究；项目3，临床研究。临床前治疗 研究(项目1)将完全在活体小鼠肿瘤中进行 模特们。一种特殊药物操作的治疗结果， 在生物化学的基础上如期获得 促使这种操纵的信息将在 生化水平(方案2)确保化疗效果 与预测的生化变化有关。生化分析 人类肿瘤的治疗前后，确定(和建立) 所用的临床剂量重现了相同的生化 对成功的临床前结果负责的变化。 因此，临床前结合了体内生物和生化 调查结果，项目1和2，导致项目3的指导方针‘S非常 具体的临床试验。

The ultimate goal of the proposed research program is the development of both safer and more effective combination therapy for cancer. Based on principles of 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. the control of serious host toxicity is viewed as essential to the achievement of chemotherapeutic cure, because the resulting operational increase in drug selectivity will allow both a quantitative and a qualitative intensification of chemotherapy. In addition to the specific "rescue" approach for antimetabolite toxicity with the corresponding normal metabolite, attempts will be made to prevent drug-induced toxicity by stimulating more rapid hematopoietic recovery between drug treatment courses with hematopoietic growth factors; also, selected agents with potential for sparing, or for stimulating more rapid recovery in drug-damaged intestinal epithelium will be evaluated. the goal is to increase both the power and selectivity of the therapeutic attack, hopefully to the level of cure of advanced, spontaneous solid cancer, first in a murine model and then ultimately in patients. This approach requires the integration of 3 projects: Project 1, Experimental Therapy; Project 2, Biochemical Studies; Project 3, Clinical Studies. Preclinical therapy studies (Project 1) will be performed entirely in vivo murine tumor models. Therapeutic results from a particular drug manipulation, obtained as expected on the basis of the basis of the biochemical information that prompted that manipulation, will be confirmed on a biochemical level (Project 2) to insure that the chemotherapeutic results are related to the predicted biochemical changes. Biochemical analysis of human tumors, before and after treatment, determine (and establish) that the employed clinical dose is reproducing the same biochemical changes that were responsible for the successful preclinical results. Thus, the preclinical combined in vivo biological and biochemical findings, Projects 1 and 2, lead to guidelines for Project 3's very specific clinical trials.