CANCER THERAPY WITH BIOCHEMICAL MODULATORS BRMS & CSFS

生化调节剂 BRMS 的癌症治疗

• 批准号: 3093107
• 负责人: DANIEL S MARTIN
• 金额: $ 111.26万
• 依托单位: ST. VINCENT CATHOLIC MEDICAL CTR NURSING
• 依托单位国家: 美国
• 财政年份: 1980
• 资助国家: 美国
• 起止时间: 1980-04-01 至 1992-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3093107
• 关键词: antineoplastics; combination chemotherapy; drug metabolism; neoplasm /cancer chemotherapy

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.

拟议的研究计划的最终目标是开发 更安全，更有效的癌症结合疗法。 基于 生化调制，药物组合或药物 - 代谢物的原理 组合，根据已知或潜在的生化选择 相互作用将用于操纵相关的生化途径 在治疗上有益的方式，以增强选择性 肿瘤细胞的细胞毒性和/或选择性降低毒性 正常的宿主细胞。 严重宿主毒性的控制被视为 对于化学治疗的实现至关重要，因为由此产生 药物选择性的运营提高将允许定量和 化学疗法的定性强化。 除了特定 与相应正常的抗代谢物毒性的“救援”方法 代谢物，将尝试防止药物引起的毒性 使用IFN，TNF或TGF-B暂时放慢造血增殖的减慢， 用造血细胞因子和和 没有EGF来刺激恢复药物受损的肠上皮。 最后，IL-2和IFN的免疫疗法将集成到 治疗方案的目的是恢复和增强免疫功能 在化学疗法减轻肿瘤负担的时候。 目标 是为了提高治疗攻击的能力和选择性， 希望达到晚期自发固体癌的治疗水平，首先 在鼠模型中，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）将完全在体内鼠肿瘤模型中进行。 特定药物操纵的治疗结果，以 根据生化信息的预期，促使 操纵，将在生化水平（项目2）上进行确认以确保 生物学结果与预测的生化有关 更改。 意外的治疗结果将在生化中探讨 提供比较药理和生化的指南 诊所的研究（项目3）将用于调整有希望的 从动物肿瘤模型翻译为的治疗药物方案 癌症患者。 体内生物学和生化发现的结合， 项目1、2，导致针对特定临床试验的准则和反馈 从临床研究中可能表明新的实验研究， 改进。