MODEL TO TEST THE THERAPEUTIC VALUE OF TOXIN CONJUGATES

测试毒素结合物治疗价值的模型

• 批准号: 3193314
• 负责人: VICTOR A RASO
• 金额: $ 24.31万
• 依托单位: BOSTON BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-12-01 至 1995-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3193314
• 关键词: antineoplastics; athymic mouse; autoradiography; chemical conjugate; cytotoxicity; diphtheria toxin; disease /disorder model; drug screening /evaluation; hybridomas; immunoglobulin G; immunoglobulin structure; immunotoxicity; iodine; laboratory mouse; ligands; mesothelioma; monoclonal antibody; neoplasm /cancer chemotherapy; peritoneal cavity; point mutation; ricin; selenium; severe combined immunodeficiency; tissue /cell culture; toxin

Aspirations to harness the lethal potency of plant and bacterial toxins for beneficial use in medicine have yet to be fully realized. Various toxins have been chemically or genetically linked with specific antibody and ligand carriers to focus their action exclusively on cancer cells. These new derivative toxins provide very potent and highly selective cell kill in vitro but their performance as therapeutic agents in animal models has continued to fall far short of expectation. Substantial deficiencies have persisted despite years of intensive effort to refine the technology for producing toxin conjugates. This continuing study has therefore been designed to identify the key factors underlying in vivo effectiveness and to furnish unique insights into tumoricidal mechanisms. It addresses this critical problem from a novel perspective by deploying a model system of advanced neoplastic disease which is curable using selective toxin therapy. Valuable information regarding the fundamentals of toxin-based therapeutics is being obtained which should facilitate the design of agents with optimal clinical effectiveness and utility. A model of human malignant mesothelioma in athymic and SCID mice is being used, since the natural resistance of murine cells allows diphtheria toxin to selectively kill the human cancer target cells and cure these mice. Thus this study will encompass patterns of malignancy which involve mainly the peritoneal cavity as well as more disseminated forms of disease. Special in vivo tumor labeling and autoradiographic techniques have been developed to measure the time course, location and extent of native toxin versus immunotoxin action on tumors in situ. Essential features are thereby being revealed which explain how a single microgram dose of native toxin can kill a billion or more cancer cells and eradicate established solid tumors weighing 1-3 gm. A new, diphtheria toxin-based hybridoma screening agent has been designed to identify the most suitable monoclonal antibodies for making potent anti-tumor cell immunotoxins. Experiments are being performed to determine the pertinent distinctions which explain discrepancies in the action of toxin conjugates and diphtheria toxin in this model. Various antibodies, antibody fragments and ligands will be linked to diphtheria toxin to determine if such modifications curtail its access to tumor cells and diminish its effectiveness. The therapeutic model will provide a frame of reference to judge the performance of modified toxins and to improve those which fail to achieve cures. This system offers a means for directly testing which structural changes obstruct the curative properties of a toxin and which are permissible.

渴望利用植物和细菌毒素的致命效力 在医学中的有益用途尚未完全实现。 各种各样的 毒素已与特定抗体有化学或遗传学联系 和配体载体将其作用专门集中在癌细胞上。 这些新的衍生毒素提供了非常有效且高度选择性的细胞 在体外杀死，但它们作为动物治疗剂的表现 模型持续远远没有期待。 重大的 尽管经过多年的精力来完善，但缺陷仍然存在 生产毒素缀合物的技术。 因此，这项持续研究旨在识别关键 体内有效性的基础因素并提供独特的见解 进入肿瘤机制。 它从一个问题中解决了这个关键问题 通过部署高级肿瘤模型系统的新观点 使用选择性毒素疗法可以治愈的疾病。 有价值的 有关基于毒素疗法的基础知识的信息是 获得的，应促进最佳的代理设计 临床有效性和效用。 无胸腺和SCID小鼠中人类恶性间皮瘤的模型正在 使用，由于鼠细胞的自然耐药性允许白喉 毒素有选择地杀死人类癌症靶细胞并治愈这些细胞 老鼠。 因此，这项研究将涵盖恶性肿瘤的模式 主要涉及腹膜腔以及更多的传播形式 疾病。 特殊体内肿瘤标签和放射自显影 已经开发了测量时间过程，位置和 天然毒素与免疫毒素作用对原位肿瘤作用的程度。 从而揭示了基本特征，这解释了一个单一的 天然毒素的微克剂量会杀死十亿或更多的癌细胞 并根除重量为1-3克的实体瘤。 一个新的， 基于白喉毒素的杂交瘤筛查剂已设计为 确定最合适的单克隆抗体 抗肿瘤细胞免疫毒素。 实验正在执行 确定相关的区别，这些区别解释了 在该模型中，毒素结合物和白喉毒素的作用。 各种各样的 抗体，抗体片段和配体将与白喉相关 毒素以确定这种修饰是否会减少其对肿瘤的访问 细胞并降低其有效性。 治疗模型将提供 判断改良毒素的性能和 改善那些无法治愈的人。 该系统提供了一种手段 直接测试哪种结构变化阻碍了治疗剂 毒素的特性和允许的特性。