BIOLOGY OF HEPATOCARCINOGENESIS

这项研究的长期目标是改进幼鼠模型 对肝癌的发生和进一步的显微特征的研究 单次注射致癌物引起的肝细胞损伤。近期 来自我的实验室的形态和动力学数据有力地表明 单次小剂量二乙基亚硝胺在幼鼠体内诱导数百例 肝细胞病灶，其中许多进展为微癌，然后 转移性小梁型肝细胞癌。因此，有 有充分的理由相信，对该模型的进一步评估可能会提供 快速评价相对致癌性、促进性和 多种环境化学物质和饮食的抗促进性 选民。 完全致癌物单次注射的效果 (二乙基亚硝胺、乙基亚硝脲、黄曲霉毒素B1和氨基甲酸乙酯) 以及启动后改良剂(卡路里限制、苯巴比妥和 肝部分切除术)对病灶生长动力学的影响将被确定。因为我们的 新的增长动力学方法非常敏感，使我们能够估计 在比较粒度分布的基础上的增长率变化 以及几个时间点的数值密度，我们应该能够 以确定某一特定影响是否影响了 肿瘤或开始生长的病灶数目的变化。这些 研究大规模疫源地种群生长动力学的技术将是 辅之以利用~3H-TdR标记的其他动力学方法的研究 指数。 在另一系列实验中，肝脏将被灌流，并进行尝试 用离心法和流式细胞术分离病灶中的肝细胞 在短期培养中种植它们。 光镜、超微结构和组织化学技术，还将 可用于研究病灶及其血管侵袭特征。 其中许多在体内和体外条件下是不同的。

The long term objective of this study is to refine the infant mouse model for hepatocarcinogenesis and further characterize the microscopic hepatocellular lesions induced by single injections of carcinogens. Recent morphologic and kinetic data from my laboratory strongly suggest that single small doses of diethylnitrosamine in infant mice induce hundreds of hepatocellular foci, many of which progress to microcarcinomas and then to metastasizing trabecular hepatocellular carcinomas. Therefore there is good reason to believe that further evaluation of the model may provide the means for rapid evaluation of the relative carcinogenic, promoting and antipromoting effects of various environmental chemicals and dietary constituents. The effects of single injections of complete carcinogens (diethylnitrosamine, ethylnitrosourea, aflatoxin B1 and ethyl carbamate) and of post-initiation modifiers (caloric restriction, phenobarbital and partial hepatectomy) on foci growth kinetics will be determined. Since our new growth kinetic methods are very sensitive and permit us to estimate changes in growth rates on the basis of a comparison of size distribution and numerical densities of foci at several time points, we should be able to determine whether a particular effect is on the rate of growth of neoplasms or on changes in the number of foci that start to grow. These techniques to study growth kinetics of large populations of foci will be complemented by studies of other kinetic methods using 3H-TdR labeling indices. In another series of experiments livers will be perfused and attempts made to separate hepatocytes in foci by centrifugation and flow cytometry and to grow them in short term cultures. Light microscopic, ultrastructural and histochemical techniques, will also be used for study of the foci and their vascular invasive features under many of these different in vivo and in vitro conditions.