Bursch W, Grasl-Kraupp B, Wastl U, Hufnagl K, Chabicovsky M, Taper H, Schulte-Hermann R
Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
Toxicol Lett. 2004 Apr 1;149(1-3):25-35. doi: 10.1016/j.toxlet.2003.12.018.
Apoptosis constitutes one of the organisms defense lines against cancer. We investigated whether failure of apoptosis may be concurrently causative for the high cancer susceptibility in C3H/He as compared to C57BL/6J mice (low cancer susceptibility). First, in short-term in vivo experiments (7-21 days), mouse liver growth (C3H/He, C57BL/6J) was induced by administration of phenobarbital (PB; 2 days 500 ppm + 5 days 750 ppm via the food) or nafenopin (NAF; 7 days 500 ppm via the food), cessation of PB or NAF treatment served to initiate liver involution. Liver weight, DNA content, hepatocyte ploidy and apoptotic activity were studied as endpoints. Secondly, in a long-term study liver carcinogenesis was initiated by a single dose of N-nitrosodiethylamine (NDEA, 90 mg/kg b.w.) to 5-weeks-old C57Bl/6J and C3H/He mice. After 2 weeks, mice received either standard diet or a diet containing phenobarbital (PB, 90 mg/kg b.w.) for up to 90 weeks. Cell proliferation and apoptosis in normal liver tissue and (pre)neoplastic tissue was quantitatively analysed by histological means. The short term studies revealed that PB and NAF-induced mouse liver growth is essentially due to cell enlargement (hypertrophy). A moderate increase of liver DNA content was brought about by hepatocellular polyploidization; C3H/He mice exhibited the most pronounced ploidy shift, corresponding to their high cancer susceptibility. Upon cessation of PB or NAF treatment, regression of liver mass was neither associated with a loss of DNA nor an increase in apoptoses in the liver of C3H/He and C57Bl/6J mice; food restriction did not enforce the occurrence of apoptosis. Thus, the mouse strains did not differ with respect to the occurrence of apoptosis. In the long-term study, PB promoted liver tumor formation in all strains, exhibiting quantitative differences in growth kinetics of preneoplasia rather than a specific biological quality. Quantitative analysis of apoptosis in normal and (pre)neoplastic liver tissue of C3H/He and C57BL/6J mice revealed no clue to explain their different cancer susceptibility. Rather, cell proliferation seems to be the prevailing determinant of tumor promotion in the liver of both mouse strains.
细胞凋亡是机体对抗癌症的防御机制之一。我们研究了与C57BL/6J小鼠（低癌症易感性）相比，C3H/He小鼠中细胞凋亡的失败是否可能同时导致其高癌症易感性。首先，在短期体内实验（7 - 21天）中，通过给予苯巴比妥（PB；经食物给药，2天500 ppm + 5天750 ppm）或萘夫平（NAF；经食物给药，7天500 ppm）诱导小鼠肝脏生长（C3H/He、C57BL/6J），停止PB或NAF治疗以启动肝脏 involution。研究肝脏重量、DNA含量、肝细胞倍性和凋亡活性作为终点指标。其次，在一项长期研究中，对5周龄的C57Bl/6J和C3H/He小鼠单次给予N - 亚硝基二乙胺（NDEA，90 mg/kg体重）以启动肝癌发生。2周后，小鼠接受标准饮食或含苯巴比妥（PB，90 mg/kg体重）的饮食，持续长达90周。通过组织学方法对正常肝脏组织和（前）肿瘤组织中的细胞增殖和凋亡进行定量分析。短期研究表明，PB和NAF诱导的小鼠肝脏生长主要是由于细胞增大（肥大）。肝细胞多倍体化导致肝脏DNA含量适度增加；C3H/He小鼠表现出最明显的倍性变化，与其高癌症易感性相对应。停止PB或NAF治疗后，C3H/He和C57Bl/6J小鼠肝脏重量的减轻既不与DNA的损失相关，也不与肝脏凋亡的增加相关；食物限制并未促使凋亡的发生。因此，在凋亡的发生方面，这两种小鼠品系没有差异。在长期研究中，PB促进了所有品系的肝脏肿瘤形成，在肿瘤前病变的生长动力学上表现出数量差异，而非特定的生物学特性。对C3H/He和C57BL/6J小鼠正常和（前）肿瘤肝脏组织中的凋亡进行定量分析，没有发现解释它们不同癌症易感性的线索。相反，细胞增殖似乎是这两种小鼠品系肝脏肿瘤促进的主要决定因素。
