EXPERIMENTAL CHEMOTHERAPY

实验性化疗

• 批准号: 3938349
• 负责人: DANIEL S MARTIN
• 金额: --
• 依托单位: ST. VINCENT CATHOLIC MEDICAL CTR NURSING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3938349
• 关键词: N phosphonoacetyl L aspartate; antimetabolites; antineoplastics; breast neoplasms; combination chemotherapy; cytidine; cytosine arabinoside; cytotoxicity; disease /disorder model; dosage; drug administration routes; drug adverse effect; drug metabolism; fluorouracil; leucovorin; lung neoplasms; methotrexate; mitomycin C; neoplasm /cancer chemotherapy; neoplasm /cancer transplantation; uridine

The objective of Project 1, Experimental Chemotherapy, is to develop clinical guidelines at the preclinical level for the optimization of anticancer drug combinations based on principles of biochemcail modulation. The rationale is to combine certain modulating and effector agents, so that the modulating agents can manipulate the existing quantitative differences among the metabolic determinants of drug action in tumor cells versus normal host cells so as to favor the antitumor action of the effector agent. Therefore, one modulating agent may be selected for combination with an effector, or cytotoxic, agent in order to increase cyctotoxicity specifically in tumor cells as opposed to normal cells, and another modulating agent (e.g., normal metabolite) may be selected for ability to protect normal cells specifically from the cytotoxic action of an effector agent ( e.g., an antimetabolite). Agents will be selected on the basis of a specific biochemical rationale and drug combinations will be assembled in a stepwise approach. In an increased antitumor effect is accompained by untoward host toxicity, the next step is the addition of an agent to selectively protect the host. This procedure continues with the addition of another drug to yield further augmentation of tumor toxicity, and so on, until the ultimate objective of cure is attained. Specific drug combinations are proposed. This approach seeks the control of serious host toxicity as essential to the achievement of chemotherapeutic cure, because the resulting operational increase in drug selectively will allow both a quantitative and a qualitative increase in the chemotherapeutic drug combination. Chemotherapy studies will be performed entirely in in vivo murine tumor models. Tumors will be advanced at initiation of treatment, and therapeutic activity will be assessed in terms of tumor growth inhibition, number of partial and complete tumor regressions, and ultimately, the most promising drug combinations will be evaluated for activity against metastatic tumor and on lifespan. Potential toxic side effects (e.g., damage to the intestinal epithelium and leukopenia) will be monitored in the same experiments. In vivo biochemical and pharmacological studies (Project 2, Biochemical Studies) in the same animal tumor models will provide guidelines for comparative pharmacological and biochemical studies in the clinic (Project 4, Clinical Studies) 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 and 2, lead to guidelines for specific clinical trails; feedback from Project 4, Clinical Studies, may suggest new experimental studies and refinements.

项目1的目的是实验化疗，是 在临床前制定临床准则 基于原理优化抗癌药物组合 生物化学调制。 理由是结合一定 调节和效应剂，以便调节剂可以 操纵现有的定量差异 肿瘤细胞中药物作用的代谢决定因素与 正常的宿主细胞以偏爱 效应剂。 因此，可以选择一个调节剂 与效应器或细胞毒性剂结合起来 在肿瘤细胞中专门提高胞毒性 正常细胞和另一个调节剂（例如，正常 可以选择代谢物）以保护正常细胞 特别来自效应剂的细胞毒性作用（例如， 抗代谢物）。 将根据 特定的生化原理和药物组合将是 以逐步方法组装。 在增加的抗肿瘤中 效果伴随着不良宿主的毒性，下一步是 添加代理以选择性保护主机。 这 程序继续添加另一种药物来产生 进一步增强肿瘤毒性，依此类推，直到 实现了治愈的最终目标。 特定的药物组合 提出了。 这种方法寻求严肃主持人的控制 毒性对于实现化学治疗至关重要 治愈，因为导致药物的运营增加 有选择地允许定量和定性 化学治疗药物组合的增加。 化学疗法研究将完全在体内鼠中进行 肿瘤模型。 肿瘤将启动 治疗和治疗活动将以 肿瘤生长抑制，部分和完全肿瘤的数量 回归，最终是最有希望的药物组合 将评估针对转移性肿瘤的活性和 寿命。 潜在的有毒副作用（例如，损害 将监测肠上皮和白细胞减少症） 相同的实验。 体内生化和药理学 研究（项目2，生化研究） 模型将为比较药理提供指南 和诊所的生化研究（项目4，临床研究） 它将用于调整有希望的治疗药物方案 用于从动物肿瘤模型转换为癌症患者。 体内生物学和生化发现，项目 1和2，导致特定临床踪迹指南；反馈 从项目4中，临床研究可能提出新的实验 研究和改进。