EXPERIMENTAL CHEMOTHERAPY

项目1，实验性化疗的目标是 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 生物化学调节。 基本原理是将联合收割机某些 调节剂和效应剂，使得调节剂可以 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 正常宿主细胞，以有利于本发明的抗肿瘤作用。 效应剂 因此，可以选择一种调节剂 用于与效应剂或细胞毒性剂组合， 增加细胞毒性，特别是在肿瘤细胞中， 正常细胞和另一种调节剂（例如，正常 代谢物）可以根据保护正常细胞的能力来选择 特别是来自效应剂的细胞毒性作用（例如， 抗代谢物）。 代理商将根据以下标准进行选择： 具体的生物化学原理和药物组合将 以逐步的方式组装。 在抗肿瘤作用增加 效果伴随着有害的宿主毒性，下一步是 添加一种药剂来选择性地保护宿主。 这 程序继续添加另一种药物， 肿瘤毒性的进一步增强，等等，直到 达到治愈的最终目的。 特定药物组合 被提议。 这种方法寻求控制严重的主机 毒性对于实现化疗至关重要 治愈，因为由此产生的药物操作增加 选择性地将允许定量和定性 化疗药物组合的增加。 化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 治疗和治疗活性将根据 肿瘤生长抑制，部分和完全肿瘤数量 回归，最终，最有前途的药物组合 将评价抗转移性肿瘤的活性， 寿命 潜在的毒副作用（例如，损坏 肠上皮细胞和白细胞减少症）将在 同样的实验。 体内生物化学和药理学 研究（项目2，生化研究） 模型将为比较药理学 临床和生化研究（项目4，临床研究） 这将用于调整有前途的治疗药物方案， 用于从动物肿瘤模型转化到癌症患者。 结合体内生物学和生物化学的发现，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，可能表明新的实验 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.