Kraupp-Grasl B, Huber W, Putz B, Gerbracht U, Schulte-Hermann R
Institut für Tumorbiologie-Krebsforschung der Universität Wien, Vienna, Austria.
Cancer Res. 1990 Jun 15;50(12):3701-8.
The involvement of tumor promotion in the hepatocarcinogenic action of peroxisome proliferators has not been generally accepted. We studied the effect of nafenopin (NAF) as a model compound in a two-stage initiation-promotion protocol. Carcinogenesis was initiated by a single dose of aflatoxin B1 (AFB1) in female (AFB1, 5 mg/kg) and male (AFB1, 2 mg/kg) Wistar rats. After recovery NAF was fed via the diet, providing a daily dose of 100 mg/kg body weight. Phenobarbital (PB) (50 mg/kg body weight) was fed to female rats as a positive control. The following results were obtained. (a) At weeks 40, 55, 59, and 70, significantly more and larger liver tumors were present in AFB1-NAF-treated rats than in rats receiving either compound alone, and the effect of the combined treatment was clearly more than additive, in three independent experiments including both sexes. This suggests tumor promotion by NAF. Male rats responded more strongly than females. Similarly, PB enhanced the yield of liver tumors. Histologically, tumors were hepatocellular adenoma or carcinoma. In group AFB1-PB the majority consisted of eosinophilic and glycogenstoring cells. However, adenoma and carcinoma of groups AFB1-NAF and O-NAF consisted of weakly basophilic cells. (b) Phenotypically altered foci were evaluated in hematoxylin- and eosin-stained liver sections from the female rats. NAF treatment after AFB1 had little effect on number and size of eosinophilic-clear cell foci and decreased the number of trigroid foci. However, it led to a dramatic increase (20-fold after 70 weeks of NAF treatment) in number and size of foci of a special phenotype that was extremely rare after AFB1 alone and virtually absent in group AFB1-PB. Hepatocytes in these foci are characterized by weak diffuse basophilia and some eosinophilia, similar to the phenotype in adenoma and carcinoma, and by absence of gamma-glutamyltranspeptidase (GGT) expression. Based on these findings, we propose the hypothesis that NAF promotes the development of liver tumors via a mechanism involving amplification of a specific subtype of altered hepatic foci.
过氧化物酶体增殖剂的促癌作用在肝癌致癌作用中的参与尚未得到普遍认可。我们以萘酚平（NAF）作为模型化合物，在两阶段启动-促癌方案中进行了研究。致癌作用通过对雌性（黄曲霉毒素B1，5毫克/千克）和雄性（黄曲霉毒素B1，2毫克/千克）Wistar大鼠单次给予黄曲霉毒素B1（AFB1）来启动。恢复后，通过饮食给予NAF，每日剂量为100毫克/千克体重。将苯巴比妥（PB）（50毫克/千克体重）给予雌性大鼠作为阳性对照。获得了以下结果。（a）在第40、55、59和70周时，AFB1-NAF处理的大鼠中出现的肝肿瘤明显比单独接受任何一种化合物处理的大鼠更多、更大，并且在包括两性的三项独立实验中，联合处理的效果明显超过相加效应。这表明NAF具有促癌作用。雄性大鼠的反应比雌性大鼠更强烈。同样，PB提高了肝肿瘤的发生率。从组织学上看，肿瘤为肝细胞腺瘤或癌。在AFB1-PB组中，大多数由嗜酸性和糖原储存细胞组成。然而，AFB1-NAF组和O-NAF组的腺瘤和癌由弱嗜碱性细胞组成。（b）对雌性大鼠苏木精和伊红染色的肝脏切片中的表型改变灶进行了评估。AFB1后给予NAF对嗜酸性-透明细胞灶的数量和大小影响不大，并减少了三叶草形灶的数量。然而，它导致一种特殊表型的灶的数量和大小急剧增加（NAF处理70周后增加20倍），这种表型在单独给予AFB1后极为罕见，在AFB1-PB组中几乎不存在。这些灶中的肝细胞的特征是弱弥漫性嗜碱性和一些嗜酸性，类似于腺瘤和癌中的表型，并且缺乏γ-谷氨酰转肽酶（GGT）表达。基于这些发现，我们提出假说，即NAF通过涉及特定亚型的改变的肝灶扩增的机制促进肝肿瘤的发展。
