MECHANISM OF ACTION OF THIABENDAZOLE

噻菌灵的作用机制

• 批准号: 3179368
• 负责人: JOEL LUNDY
• 金额: $ 6万
• 依托单位: NYU WINTHROP HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-09-01 至 1986-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3179368
• 关键词: bacterial polysaccharides; benzimidazoles; bone marrow transplantation; cell differentiation; cellular immunity; combination cancer therapy; drug metabolism; electrofocusing; hematopoiesis; hematopoietic growth factor; hematopoietic stem cells; immunodeficiency; leukopoiesis; radiotracer

The general scientific goals of the project are to test the hypothesis that the immunomodulating agent thiabendazole (TBZ), when given in conjunction with a thymus-dependent antigen, promotes the production of ahumoral factor(s) (lymphohemopoietic stimulating factor, LHSF) which affects the proliferation and differentiation of primitive lymphopoietic and hemopoietic cells. The following progress has been made in the first year of the grant. We have initiated experiments to determine whether other thymus-dependent antigens, in addition to DNFB, can act synergistically with TBS to stimulate lymphohemopoiesis in normal mice. The results indicate that oxazolone, another skin-sensitizing antigen, is also effective, whereas KLH is not. We now plan to screen a battery of thymus-dependent antigens to determine if only those having skin-sensitizing properties are active in the generation of the LHSF. The results of these studies may have important clinical implications, if indeed skin-sensitizing antigens are required for the maximum therapeutic efficacy of TBZ and closely related compounds. We have initiated experiments to determine whether TBZ and DNFB stimulate lymphohemopoiesis in congenitally athymic (nude) mice. Thus far we have not observed any effect. This suggests that T lymphocytes may be important in the generation of the LHSF. We plan to formally test this by reciprocal cell transfer and serum transfer experiments between normal and nude mice injected with TBZ and/or DNFB. These experiments should also reveal whether LHSF is composed of two factors, one produced by antigen-stimulated T cells (and therefore absent from nude mice) and one produced by TBZ-stimulated macrophages (and therefore present in nude mice). We have improved the assay for TdT-positive cells by changing from immunofluorescence to immunoperoxidase. The results are not only more quantifiable but also the preparations are permanent and available for retrospective analysis if necessary. We have also initiated studies using 50H-TBZ, the active metabolite of TBZ. This should make the experimental system more dose-responsive by eliminating the need to work with the highly insoluble form of TBZ. (IT)

该项目的总体科学目标是检验以下假设： 免疫调节剂噻菌灵 (TBZ)，联合使用时 具有胸腺依赖性抗原，促进非体液的产生 影响淋巴细胞生成的因子（淋巴造血刺激因子，LHSF） 原始淋巴细胞的增殖和分化 造血细胞。 第一年取得了以下进展 的补助金。 我们已经启动了实验来确定是否有其他胸腺依赖性 除 DNFB 外，抗原还可与 TBS 协同作用， 刺激正常小鼠的淋巴造血作用。 结果表明 另一种皮肤致敏抗原恶唑酮也有效，而 KLH 不是。 我们现在计划筛选一组胸腺依赖性抗原 确定是否只有那些具有皮肤敏感特性的物质才具有活性 LHSF 的产生。 这些研究的结果可能有 如果皮肤致敏抗原确实存在，则具有重要的临床意义 TBZ 发挥最大疗效所需的物质和密切相关 化合物。 我们已经开始实验来确定 TBZ 和 DNFB 是否会刺激 先天性无胸腺（裸鼠）小鼠的淋巴造血作用。 到目前为止我们已经 没有观察到任何效果。 这表明 T 淋巴细胞可能很重要 在 LHSF 的产生中。 我们计划通过互惠来正式测试这一点 正常小鼠与裸鼠之间的细胞转移和血清转移实验 注射TBZ和/或DNFB。 这些实验还应该揭示 LHSF是否由两种因素组成，一种是由抗原刺激产生的 T 细胞（因此裸鼠中不存在）和由 TBZ 刺激巨噬细胞（因此存在于裸鼠中）。 我们改进了 TdT 阳性细胞的检测方法，将 免疫荧光免疫过氧化物酶。 结果不仅更多 可以量化，而且准备工作是永久性的并且可以用于 必要时进行回顾性分析。 我们还启动了研究，使用 50H-TBZ，TBZ 的活性代谢物。 这应该使实验 通过消除与高度工作的需要，系统更具剂量响应性 TBZ 的不溶形式。 （它）