CANCER THERAPY WITH BIOCHEMICAL MODULATORS BRMS & 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 根据已知或潜在的生化指标选择的组合 相互作用，将被用来操纵相关的生化途径 一种有益于治疗的方式来增强选择性 对肿瘤细胞的细胞毒性，和/或选择性地降低肿瘤细胞的毒性 正常的宿主细胞。严重寄主毒性的控制被认为是 对实现化疗治愈至关重要，因为由此产生的 操作上药物选择性的增加将允许数量和 化疗的质的强化。除了具体的 抗代谢药物毒性的“抢救”方法及相应的正常 代谢物，将试图通过以下方式预防药物引起的毒性 干扰素、肿瘤坏死因子或转化生长因子-β对造血细胞增殖的暂时性减缓 用造血细胞因子刺激更快的恢复 不加EGF刺激药物损伤的肠上皮细胞恢复。 最后，IL-2和干扰素的免疫治疗将整合到 以恢复和增强免疫功能为目的的治疗方案 在化疗减轻了肿瘤负担的情况下。目标是 是为了增加治疗性攻击的威力和选择性， 希望达到晚期自发性实体癌的治愈水平，首先 在小鼠模型中，然后最终在病人身上。这种方法需要 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模型中进行。 从特定的药物操作中获得的治疗结果，如 根据促使生物化学的信息 操作，将在生化水平上进行确认(项目2)以确保 生物结果与预测的生化结果有关 改变。意想不到的治疗结果将在生化展上被探索 为比较药理和生化水平提供指导方针 临床研究(项目3)，将用于调整前景 将动物肿瘤模型转化为的治疗药物方案 癌症患者。结合了体内生物和生化的发现， 项目1、2，为具体的临床试验和反馈提供指南 可能会提出新的实验研究和 精益求精。

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 through temporary slowing of hematopoietic proliferation with IFN, TNF or TGF-B, and to stimulate more rapid recovery with hematopoietic cytokines with and without EGF to stimulate recovery of drug damaged intestinal epithelium. Finally, immunotherapy with IL-2 and IFN will be integrated into the therapeutic regimen with the aim of restoring and enhancing immune function at a time when the tumor burden has been reduced by chemotherapy. 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 biochemical information that prompted that manipulation, 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 guidelines for comparative pharmacological and biochemical studies in the clinic (Project 3) 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.