EXPERIMENTAL CHEMOTHERAPY

项目1的目标，实验疗法，是制定指导方针， 在临床前水平优化抗癌药物 基于生物化学调节原理的应用组合 在诊所里 调节剂和效应剂将被组合， 代谢决定因素之间存在的数量差异 药物在肿瘤细胞中的作用与正常宿主细胞相比将被放大， 以有利于效应剂的抗肿瘤作用。 因此，一 可以选择调节剂与效应物组合，或 细胞毒性剂，以增加特异性肿瘤细胞毒性 与正常细胞相反的细胞，和另一种调节剂（例如，正常 代谢物）可以根据特异性保护正常细胞的能力来选择 来自效应物的细胞毒性作用（例如，抗代谢物）。 剂 将根据特定的生物化学原理和药物选择 组合将以逐步的方式组装。 如果增加 抗肿瘤作用伴随着不利的宿主毒性，下一步是 添加一种药剂来选择性地保护宿主。 除了 抗代谢药毒性的特定“补救”方法， 相应的正常代谢产物，将尝试防止 通过暂时减缓增殖的药物诱导毒性， 造血前体与IFN、TNF或TGF-B，以及刺激 用造血细胞因子（IL-1 + GM-CSF和/或IL-3， IL-4和IL-6）。 EGF将被评估（与CSF），以刺激恢复 药物治疗后的肠上皮。 最后，免疫疗法， IL-2和IFN将与治疗方案整合，目的是 恢复和增强免疫功能的时候，肿瘤负担已经 因化疗而减少。 此过程继续添加 另一种药物来进一步增强肿瘤毒性，等等， 直至达到治愈的最终目的。 特定药物 提出了组合。 这种方法寻求控制严重的主机 毒性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 化疗药物的量和质的增加 组合. 治疗研究将完全在体内小鼠中进行。 肿瘤模型 肿瘤将在治疗开始时进展，并且 治疗活性将根据肿瘤生长抑制来评估， 部分和完全肿瘤消退的数量，最终， 将评估有希望的药物组合的活性， 转移性肿瘤和对寿命的影响。 潜在毒副作用 (e.g.,肠上皮损伤和白细胞减少症 在同样的实验中。 所有拟议研究的重点是 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.