EXPERIMENTAL THERAPY

实验治疗

• 批准号: 3749506
• 负责人: DANIEL S MARTIN
• 金额: --
• 依托单位: CATHOLIC MEDICAL CTR OF BKLYN & QUEENS
• 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/3749506
• 关键词: DNA damage; N phosphonoacetyl L aspartate; adenosine triphosphate; antimetabolites; antineoplastics; apoptosis; breast neoplasms; buthionine sulfoximine; combination cancer therapy; combination therapy; disease /disorder model; doxorubicin; drug adverse effect; drug interactions; drug screening /evaluation; etoposide; female; laboratory mouse; mitomycins; neoplasm /cancer radiation therapy; nonhuman therapy evaluation; suramin; vitamin antagonist; DNA damage; N phosphonoacetyl L aspartate; adenosine triphosphate; antimetabolites; antineoplastics; apoptosis; breast neoplasms; buthionine sulfoximine; combination cancer therapy; combination therapy; disease /disorder model; doxorubicin; drug adverse effect; drug interactions; drug screening /evaluation; etoposide; female; laboratory mouse; mitomycins; neoplasm /cancer radiation therapy; nonhuman therapy evaluation; suramin; vitamin antagonist

The objective of Project 1, Experimental Therapy, is to develop guidelines at the preclinical level for optimization of anticancer drug combination based on principles of biochemical modulation for application in clinic. Modulating agents and effector agents will be combined so that the existing quantitative differences among the metabolic determinant of drug action in tumor cells versus normal host cells will be magnified 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 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. 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 stimulate more rapid recovery with hematopoietic cytokines, and selected agents will be evaluated to stimulate recovery of intestinal epithelium after drug treatment. 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, including a conceptually new type of modulation (achieved with a 3-drug combination, PALA + MMPR + 6-AN) aimed at amplification of the biochemical changes associated with "programmed cell death' or apoptosis resulting from treatment with many different useful chemotherapeutic drugs. 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 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 evaluatd 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.

项目1的目的是实验疗法，是为了发展 临床前的指南优化抗癌药物 基于生化调制原理的组合 在诊所。 调节剂和效应剂将合并 代谢之间的现有定量差异 肿瘤细胞中药物作用与正常宿主细胞的决定因素将 放大以有利于效应剂的抗肿瘤作用。 因此，可以选择一种调节剂与 效应子或细胞毒性剂，以增加细胞毒性 特别是在肿瘤细胞中，而不是正常细胞，另一个 可以选择调节剂（例如，正常代谢物）以提高能力 专门保护正常细胞免受细胞毒性作用 效应剂（例如抗代谢物）。 代理商将在 特定的生化原理和药物组合的基础是 以逐步方法组装。 如果增加的抗肿瘤效应是 伴随着不愉快的宿主毒性，下一步是添加 选择性保护主机的代理。 除了特定 与相应的抗代谢物毒性的“救援”方法 正常代谢物，将尝试刺激更快恢复 使用造血细胞因子，并将选定的剂评估为 刺激药物治疗后肠上皮的恢复。 这 添加另一种药物以进一步产生的程序继续 肿瘤毒性的增强等等，直到最终目标 获得治愈的方法。 提出了特定的药物组合，包括 从概念上讲，新型的调制（使用3级药物实现 组合，pala + mmpr + 6-an）旨在放大 与“程序性细胞死亡”或凋亡相关的生化变化 由许多不同有用的化学治疗的治疗导致 毒品。 这种方法寻求对严重宿主毒性的控制 对于化学治疗的实现至关重要，因为 导致药物选择性的运营提高将允许 化学治疗药物的定量和质量增加 组合。 治疗研究将完全在体内鼠进行 肿瘤模型。 肿瘤将在启动治疗时进展，并 治疗活性将根据肿瘤生长评估 抑制作用，部分和完全肿瘤回归的数量，以及 最终，最有希望的药物组合将被评估 针对转移性肿瘤的活性和对寿命的影响。 潜在的 有毒副作用（例如，肠上皮损坏 白细胞减少症）将在同一实验中进行监测。 强调所有人 拟议的研究是针对治疗选择性的优化， 而不仅仅是为了效力。