EXPERIMENTAL CHEMOTHERAPY

项目1，实验疗法的目标是制定指南 在临床前水平上优化抗癌药物 基于生化调制原理的组合应用 在诊所里。调节剂和效应剂将结合在一起 新陈代谢决定因素之间存在的数量差异 肿瘤细胞中药物作用相对于正常宿主细胞的作用将被放大 从而有利于效应剂的抗肿瘤作用。因此，一个 可以选择调制剂与效应器组合，或者 细胞毒剂，以增加对肿瘤的细胞毒作用 与正常细胞相反的细胞，以及另一种调节剂(例如，正常 代谢物)可以选择用于特定地保护正常细胞的能力 通过效应器的细胞毒性作用(例如，抗代谢药物)。代理 将根据特定的生化原理和药物进行选择 组合将以循序渐进的方式组装起来。如果增加了 抗肿瘤作用伴随着不良的宿主毒性，下一步是 添加代理以选择性地保护主机。除了……之外 抗代谢药物毒性的特殊“拯救”方法 相应的正常代谢物，将尝试防止 药物毒性通过暂时性减缓细胞增殖而引起 造血祖细胞与干扰素、肿瘤坏死因子或转化生长因子-β以及刺激 使用造血细胞因子(IL-1+GM-CSF和/或IL-3， IL-4和IL-6)。将评估EGF(与CSF一起)以刺激 药物治疗后的肠上皮细胞。最后，免疫疗法与 IL-2和干扰素将与治疗方案整合，目的是 在恢复和增强免疫功能的同时，肿瘤负担已经 因化疗而减少。此过程继续进行，添加了 另一种产生进一步增强肿瘤毒性的药物，等等， 直到达到治愈的最终目标。特效药 提出了组合方案。这种方法寻求对严肃的东道主的控制 毒性是实现化疗治愈的关键，因为 由此带来的药物选择性的运营增加将使 化疗药物的数量和质量的增加 组合。治疗研究将完全在体内小鼠身上进行 肿瘤模型。肿瘤将在治疗开始时进展，并且 治疗活性将通过抑制肿瘤生长来评估， 部分和完全肿瘤消退的数量，最终是 将对有前景的药物组合进行活性评估 对于转移的肿瘤和对寿命的影响。潜在的毒副作用 (例如，肠道上皮损伤和白细胞减少症)将受到监测 在相同的实验中。所有拟议研究的重点都是 优化治疗选择性，而不仅仅是效力。

The objective of Project 1, Experimental Therapy, is to develop guidelines at the preclinical level for the optimization of anticancer drug combinations based on principles of biochemical modulation for application in the clinic. Modulating agents and effector agents will be combined so that the existing quantitative differences among the metabolic determinants of drug action in tumor cells versus normal host cells will be magnified 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 cytotoxicity 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 (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. If an increased antitumor effect is accompanied by untoward host toxicity, the next step is the addition of an agent to selectively protect the host. 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 proliferation in hematopoietic precursors with IFN, TNF or TGF-B, as well as to stimulate more rapid recovery with hematopoietic cytokines (IL-1 + GM-CSF and/or IL-3, IL-4 and IL-6). EGF will be evaluated (with CSFs) to stimulate recovery of intestinal epithelium after drug treatment. Finally, immunotherapy with IL-2 and IFN will be integrated with the therapeutic regimen with the aim of restoring and enhancing immune function at a time the tumor burden has been reduced by chemotherapy. 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 selectivity will allow both a quantitative and a qualitative increase in the chemotherapeutic drug combination. Therapy 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 for effect on lifespan. Potential toxic side effects (e.g., damage to the intestinal epithelium and leukopenia) will be monitored in the same experiments. Emphasis in all of the proposed studies is on optimization for therapeutic selectivity, and not merely for potency.