ANTITUMOR ACTIVE COMPONENTS OF BCG CELL WALLS

研究是一种实验动物模型， 附着在油滴上的牛卡介苗和耻垢分枝杆菌细胞壁 使已形成的肿瘤消退并消除区域淋巴结 当病灶内注射时转移。 从这些衍生的组件 壁目前在兽医和人类医学中临床使用， 用于治疗癌症的免疫抑制剂。 的组件 这些在肿瘤消退中有效的细胞壁包括 细胞壁和糖脂的阿拉伯半乳聚糖-肽聚糖复合物 其游离脂质提取物的成分。 两种组分均含有酯化的 分枝菌酸，已经发现其对于有效的 疗法 以前的工作已经导致了完整的结构 对M.同时， 一个综合的发展。 的结构特点是各种塔 活性所必需阿拉伯半乳聚糖-肽聚糖复合物具有 未被确认。 本研究的总体目标是从结构上 表征阿拉伯半乳聚糖-肽聚糖复合物并鉴定 佐剂所必需复合物的结构特征 活动 阿拉伯半乳聚糖的结构表征将在 通过还原裂解技术，一种新的程序， 在本实验室期间开发的多糖结构测定 过去的补助期。 几种分枝杆菌阿拉伯半乳聚糖将 通过总还原裂解、呋喃糖特异性还原裂解检查 和部分还原裂解，如此形成的片段将被 通过质谱法和NMR光谱法分离和表征。 结构特征的识别 佐剂所必需阿拉伯半乳聚糖-肽聚糖复合物 活动将通过建立 肽聚糖衍生的糖肽和“肽-糖脂”作为肽聚糖衍生的糖肽和“肽-糖脂”形成。 这是培养的巨噬细胞对细菌细胞壁“加工”的结果。 在过去的资助期间的研究表明，培养的小鼠 巨噬细胞迅速分解肽聚糖并释放糖肽 已知具有杀真菌活性。 放射性标记研究还建立了 肽聚糖的片段保留在巨噬细胞中 膜作为共价脂质衍生物。 隔离和结构 这些衍生物的特性将继续努力， 了解巨噬细胞参与免疫调节功能。

Studies is an experimental animal model have establishd that Mycobacterium bovis BCG and Mycobacterium smegmatis cell walls attached to oil droplets cause established tumors to regress and eliminate regional lymph node metastases when injected intralesionally. Components derived from these walls are currently in clinical use in veterinary and human medicine as immunotherapeutic agents for the treatment of cancer. The components of these cell walls that are effective in tumor regression include the arabinogalactan-peptidoglycan complex of the cell wall and a glycolipid constituent of its free lipid extract. Both components contain esterified mycolic acids, which have been found to be essential for effective therapy. Previous work has resulted in the complete structural characterization of the mycolic acids from M. smegmatis as well as the development of a general synthesis. The structural features of the arabinogalactan-peptidoglycan complex that are requisite for activity have not been identified. The overall objective of this proposed research is to structurally characterize the arabinogalactan-peptidoglycan complex and identify the structural features of that complex that are requisite for adjuvant activity. Structural characterization of the arabinogalactan will be accomplished by the reductive cleavage technique, a new procedure for polysaccharide structure determination developed in this laboratory during the past grant period. Several mycobacterial arabinogalactans will be examined by total reductive cleavage, furanose-specific reductive cleavage and partial reductive cleavage and the fragments so-formed will be separated and characterized by mass spectrometry and NMR spectroscopy. Identification of the structural features of the arabinogalactan-peptidoglycan complex that are requisite for adjuvant activity will be accomplished by establishing the structures of the peptidoglycan-derived glycopeptides and "peptido-glycolipids" formed as a result of "processing" of the bacterial cell wall by cultured macrophages. Studies during the past grant period have demonstrated that cultured murine macrophages rapidly catabolize peptidoglycan and release glycopeptides known to be adjuvant-active. Radiolabeling studies have also established that fragments of the peptidoglycan are retained in the macrophage membranes as covalent lipid derivatives. The isolation and structural characterization of these derivatives will be pursued in an effort to understand macrophage involvement in immunoregulatory functions.