ANTITUMOR ACTIVE COMPONENTS OF BCG CELL WALLS

研究建立了分枝杆菌的实验动物模型 牛卡介苗和污垢分枝杆菌附着在油滴上的细胞壁 使已建立的肿瘤消退并消除区域淋巴结 瘤内注射时发生转移。派生自这些组件的组件 墙体目前在兽医和人类医学中的临床应用 用于治疗癌症的免疫治疗剂。的组件 这些在肿瘤消退中有效的细胞壁包括 阿拉伯半乳糖-肽聚糖复合体的细胞壁和糖脂 其游离脂提取物的成分。这两种成分都含有酯化 霉菌酸，已被发现是有效的 心理治疗。以前的工作已经导致了完整的结构 耻垢分枝杆菌真菌酸的性质及产生量 开发了一种通用的综合方法。的结构特征。 活性所必需的阿拉伯半乳糖-肽多聚糖复合体有 没有被确认身份。 这项拟议研究的总体目标是在结构上 鉴定阿拉伯半乳糖-肽聚糖复合体并鉴定 佐剂所必需复合体的结构特征 活动。阿拉伯半乳聚糖的结构表征如下 通过还原卵裂技术完成的，一种新的 本实验室开展的多糖结构测定是在 过去的授权期。几种阿拉伯半乳分枝杆菌将是 通过全还原裂解、呋喃糖特定的还原裂解进行检查 部分还原裂解和如此形成的碎片将被 用质谱学和核磁共振波谱对其进行了分离和表征。 结构特征的识别 佐剂必需的阿拉伯半乳糖-肽多聚糖复合体 活动将通过建立 由肽多聚糖衍生的糖肽和“肽-糖脂”形成 培养的巨噬细胞对细菌细胞壁进行“加工”的结果。 在过去的赠款期间的研究表明，培养的小鼠 巨噬细胞迅速分解代谢肽多糖并释放糖肽 已知具有佐剂活性。放射性标记研究也建立了 肽聚糖的片段被保留在巨噬细胞中 作为共价脂质衍生物的膜。隔离性与结构性 将对这些衍生品进行表征，以努力 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.