Hara A, Yoshimi N, Yamada Y, Matsunaga K, Kawabata K, Sugie S, Mori H
Department of Pathology, Gifu University School of Medicine, Japan.
Br J Cancer. 2000 Jan;82(2):467-71. doi: 10.1054/bjoc.1999.0944.
The present study was designed to investigate the effect of Fas-mediated liver cell apoptosis, induced by a hamster monoclonal antibody against mouse Fas antigen, on diethylnitrosamine (DEN)-induced hepatocarcinogenesis in mice. DEN (10 microg g(-1), intraperitoneally (i.p.)) was given to 15-day-old male C3H/HeJ mice. Three weeks after DEN treatment, Fas-mediated liver cell apoptosis induced by anti-Fas antibody resulted in a biphasic effect on induction of liver cell tumours, depending on dosage and time of antibody administration. Single or multiple treatment with high dose anti-Fas antibody (5 microg animal(-1)), induced gross liver cell damage and decreased the incidence of liver cell tumours in DEN-treated mice. In contrast, five treatments with low dose anti-Fas antibody (2 microg animal(-1)), induced dispersed localized liver cell damage and promoted the number of large-sized liver cell adenomas and hepatocellular carcinomas. These findings suggest that high dose anti-Fas antibody has a marked effect on the clearance of DEN-initiated liver cells, whereas repeated administration of low dose anti-Fas antibody promotes hepatocarcinogenesis. It is concluded that Fas-mediated liver cell apoptosis has a biphasic effect on hepatocarcinogenesis.
本研究旨在探讨由抗小鼠Fas抗原的仓鼠单克隆抗体诱导的Fas介导的肝细胞凋亡对二乙基亚硝胺（DEN）诱导的小鼠肝癌发生的影响。将DEN（10μg g(-1)，腹腔注射（i.p.））给予15日龄雄性C3H/HeJ小鼠。DEN处理3周后，抗Fas抗体诱导的Fas介导的肝细胞凋亡对肝细胞肿瘤的诱导产生双相效应，这取决于抗体给药的剂量和时间。高剂量抗Fas抗体（5μg动物(-1)）单次或多次处理会导致明显的肝细胞损伤，并降低DEN处理小鼠的肝细胞肿瘤发生率。相反，低剂量抗Fas抗体（2μg动物(-1)）五次处理会导致分散的局部肝细胞损伤，并促进大型肝细胞腺瘤和肝细胞癌的数量增加。这些发现表明，高剂量抗Fas抗体对DEN启动的肝细胞清除有显著影响，而低剂量抗Fas抗体的重复给药会促进肝癌发生。结论是，Fas介导的肝细胞凋亡对肝癌发生有双相效应。
