Kaneko Masahiro, Morimura Keiichirou, Nishikawa Takayuki, Wanibuchi Hideki, Takada Nobuyasu, Osugi Harushi, Kinoshita Hiroaki, Fukushima Shoji
Department of Pathology, Osaka City University Medical School, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
Carcinogenesis. 2002 Oct;23(10):1729-35. doi: 10.1093/carcin/23.10.1729.
Human beings are exposed to a multitude of carcinogens in their environment, and most cancers are considered to be chemically induced. Here we examined differences in genetic alterations in rat forestomach tumors induced by repeated exposure to a genotoxic carcinogen, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) or N-methylnitrosourethane (MNUR), and chronic treatment with a non-genotoxic carcinogen, butylated hydroxyanisole (BHA) or caffeic acid (CA). A total of 132, 6-week-old male F344 rats were employed. Forty rats were treated with MNNG by intragastric administration at a dose of 20 mg/kg body wt once a week for 32 weeks, and 20 rats received 20 p.p.m. MNUR in their drinking water for 48 weeks. Further groups of 20 animals were administered 2% BHA or 2% CA in the diet for 104 weeks. The remaining rats were maintained without any supplement as controls. Multiple forestomach tumors were observed in all rats of the MNNG-, MNUR-, BHA- and CA-treated groups. Histopathologically, MNUR- and CA-treated groups showed almost the same pattern. On polymerase chain reaction-single strand conformation polymorphism analysis, H-ras and p53 gene mutations were observed at high and relatively low frequencies, respectively, in forestomach tumors induced by MNNG and MNUR. Most H-ras gene mutations were G-->A transitions in codons 7 and 12 of exon 1. On the other hand, forestomach tumors due to the non-genotoxic carcinogens, BHA and CA, had almost no mutations of the H-ras and p53 genes. Moreover, relative overexpression of cyclin D1 and p53 was detected in forestomach tumors induced by the genotoxic carcinogens, while their non-genotoxic counterparts had a tendency to show low expression of those molecules. Mutations of the beta-catenin gene were not detected in any group. The present study demonstrates that rat forestomach tumors induced by genotoxic and non-genotoxic carcinogens have different underlying genetic alterations, even if their pathological features are similar.
人类在其环境中会接触到多种致癌物，大多数癌症被认为是化学诱导的。在此，我们研究了反复接触基因毒性致癌物N-甲基-N'-硝基-N-亚硝基胍（MNNG）或N-甲基亚硝基脲（MNUR）以及用非基因毒性致癌物丁基羟基茴香醚（BHA）或咖啡酸（CA）进行慢性处理所诱导的大鼠前胃肿瘤的基因改变差异。总共使用了132只6周龄的雄性F344大鼠。40只大鼠每周一次经胃内给予剂量为20 mg/kg体重的MNNG，持续32周，20只大鼠在其饮用水中接受20 ppm的MNUR，持续48周。另外每组20只动物在饮食中给予2%的BHA或2%的CA，持续104周。其余大鼠不给予任何补充剂作为对照。在MNNG、MNUR、BHA和CA处理组的所有大鼠中均观察到多个前胃肿瘤。组织病理学上，MNUR和CA处理组显示出几乎相同的模式。在聚合酶链反应-单链构象多态性分析中，在MNNG和MNUR诱导的前胃肿瘤中分别以高频率和相对低频率观察到H-ras和p53基因突变。大多数H-ras基因突变是外显子1第7和12密码子中的G→A转换。另一方面，由非基因毒性致癌物BHA和CA引起的前胃肿瘤几乎没有H-ras和p53基因的突变。此外，在基因毒性致癌物诱导的前胃肿瘤中检测到细胞周期蛋白D1和p53的相对过表达，而它们的非基因毒性对应物则倾向于显示这些分子的低表达。在任何组中均未检测到β-连环蛋白基因的突变。本研究表明，即使基因毒性和非基因毒性致癌物诱导的大鼠前胃肿瘤的病理特征相似，它们的潜在基因改变也不同。
