GLYCOLIPID CHANGES DURING CHEMICAL HEPATOCARCINOGENESIS

鞘糖脂（糖脂）是膜结合的细胞表面抗原 几乎存在于所有脊椎动物的组织中。 的结构修饰 最初观察到碳水化合物部分与末端- 阶段性肿瘤发生。 随后，这些变化被证明是 在化学致癌的癌前阶段。 因此，糖脂 改变可能在化学过程中具有功能意义， 致癌作用 本文提出的研究，以加强对性质的理解， 化学性肝癌发生过程中糖脂的变化。 出发 从传统的致癌研究需要利用彩虹 鳟鱼。 对鳟鱼的研究将允许开发 这个模型系统。 第一代实验包括整个动物 用N-甲基-N '-硝基-N-亚硝基胍（MNNG）进行的肿瘤诱导研究， 阐明整个癌变过程中特定糖脂的变化。 这些 实验将使用高剂量的致癌物，以确保足够的肿瘤 用于表征糖脂改变的组织。 二代 实验将遵循传统的完全致癌作用， 与MNNG一起启动/升级团。 灵敏的探针， 第一代实验将用于阐明个体发育的 这些变化。 与这些实验巧合的是， 发展中病变的组织学研究（癌前病变， 终末期肿瘤）。 因此，将有可能确定 糖脂谱改变的特定病变类型。 糖脂将 从正常和癌前组织、肿瘤和 细胞系以及胎儿、发育和再生肝脏。 从该等 比较糖脂变化的性质和程度 测定 与这些改变相关的酶损伤将 然后进行调查，以确定这种修改的方式， 碳水化合物结构是介导的。 最后，收集的关于糖脂变化的信息， 虹鳟鱼的化学致癌作用将被仔细比较， 与已发表的哺乳动物研究相比， 进一步了解糖脂在 所有脊椎动物物种的致癌作用。

Glycosphingolipids (glycolipids) are membrane bound cell surface antigens occurring in nearly all vertebrate tissues. Structural modifications of the carbohydrate moiety were originally observed in association with end- stage tumorigenesis. Subsequently, these changes were shown to appear during a premalignant stage of chemical carcinogenesis. Thus, glycolipid alterations may be of functional significance during chemical carcinogenesis. Proposed herein are studies to enhance understanding of the nature of glycolipid alterations during chemical hepatocarcinogenesis. A departure from traditional carcinogenesis studies entails utilization of rainbow trout. Studies with trout will permit exploitation of novel aspects of this model system. First generations experiments include whole animal tumor induction studies with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) to elucidate specific glycolipid changes throughout carcinogenesis. These experiments will utilize high doses of carcinogen to insure adequate tumor tissue for characterizing glycolipid alterations. Second generation experiments will follow traditional complete carcinogenesis as well as initiation/promotion regiments with MNNG. Sensitive probes developed from the first generation experiments will be used to elucidate the ontogeny of these alterations. Coincident with these experiments will be detailed study of the histology of developing lesions (preneoplastic foci through end-stage tumors). Thus, it will be possible ascertain the specificity of particular lesion types with altered glycolipid profiles. Glycolipids will be isolated and examined from normal and premalignant tissues, tumors, and cell lines as well as fetal, developing, and regenerating liver. From such comparisons the nature and extent of glycolipid alterations will be determined. The enzymatic lesion(s) associated with these alterations will then be investigated to ascertain the manner in which such modifications in carbohydrate structure are mediated. Finally, information collected concerning glycolipid changes during chemical carcinogenesis in the rainbow trout will be carefully compared and contrasted with published mammalian studies to provide a broader base for further understanding of the significant role of glycolipids during carcinogenesis in all vertebrate species.