CANCER THERAPY WITH BIOCHEMICAL MODULATORS BRMS & CSFS

拟议研究计划的最终目标是开发 更安全和更有效的癌症联合治疗。 基于 生物化学调节、药物组合或药物代谢物的原理 组合，基于已知或潜在的生物化学 相互作用，将用于操纵相关的生化途径， 一种治疗上有益的方式， 细胞毒性，和/或选择性地减少肿瘤细胞中的毒性。 正常的宿主细胞 控制严重的宿主毒性被视为 对于实现化疗治愈至关重要，因为由此产生的 药物选择性的操作增加将允许定量和 化疗的质量强化。 除了特定的 抗代谢药毒性的“补救”方法， 代谢物，将尝试通过以下途径预防药物诱导的毒性： 用IFN、TNF或TGF-β暂时减缓造血增殖，和 用造血细胞因子刺激更快的恢复， 没有EGF刺激药物损伤的肠上皮细胞的恢复。 最后，IL-2和IFN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 此时肿瘤负荷已通过化疗减轻。 目标 是增加治疗攻击的力量和选择性， 希望能达到治愈晚期自发性实体癌的水平， 在小鼠模型中，然后最终在患者中。 这种方法需要 3个项目的整合：项目1，实验疗法;项目2， 生化研究;项目3，临床研究。 临床前治疗 研究（项目1）将完全在体内小鼠肿瘤模型中进行。 通过特定药物操作获得的治疗结果， 根据生化信息， 操作，将在生化水平上得到确认（项目2），以确保 生物学结果与预测的生物化学结果有关， 变化 意想不到的治疗结果将在生物化学实验室进行探索。 水平，为比较药理学和生物化学 临床研究（项目3），将用于调整有希望的 用于从动物肿瘤模型转化为 癌症患者。 结合体内生物学和生物化学发现， 项目1，2，导致具体的临床试验和反馈的指导方针 临床研究可能会提出新的实验研究， 改进。

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.