EXPERIMENTAL CHEMOTHERAPY

项目1，实验化疗的目标是 制定临床前水平的临床指南 基于原则的抗癌药物组合优化 生物化学的调节作用。其基本原理是将某些 调节剂和效应剂，以便调节剂可以 操纵现有的数量差异， 肿瘤细胞中药物作用的代谢决定因素与 从而有利于正常宿主细胞的抗肿瘤作用 效应剂。因此，可以选择一种调制剂 用于与效应器或细胞毒性试剂结合，以便 增加肿瘤细胞的细胞毒性，而不是 正常细胞和另一种调节剂(例如，正常 代谢物)可用于保护正常细胞的能力 特别是通过效应剂的细胞毒性作用(例如， 一种抗代谢药)。将根据以下条件选择代理 具体的生化原理和药物组合将是 以循序渐进的方式组装起来。在增强的抗肿瘤作用中 效果伴随着不良的寄主毒性，下一步是 添加代理以选择性地保护主机。这 程序继续，添加另一种药物以产生 肿瘤毒性的进一步增强，等等，直到 达到了治愈的最终目的。特定药物组合 都被提出了。这种方法寻求对严肃的东道主的控制 毒性是实现化疗的关键 治愈，因为由此导致的药物运营量增加 选择性地将允许定量和定性的 增加化疗药物组合。 化疗研究将完全在体内小鼠身上进行 肿瘤模型。肿瘤将在启动时进展 治疗和治疗活动将根据以下方面进行评估 肿瘤生长抑制、部分和完全性肿瘤数目 回归，最终，最有希望的药物组合 将被评估为抗转移肿瘤的活性以及其他 寿命。潜在毒副作用(例如，对 肠道上皮细胞和白细胞减少症)将在 同样的实验。体内生化和药理学 同一动物肿瘤的研究(项目2，生化研究) 模型将为比较药理学提供指南 临床中的生化研究(项目4，临床研究) 它将被用于调整有希望的治疗药物方案 从动物肿瘤模型移植到癌症患者身上。 结合体内生物学和生化的发现，项目 1和2，导致特定临床试验的指南；反馈 来自项目4，临床研究，可能会建议新的实验 研究和改进。

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.