Mizoguchi M, Naito H, Kurata Y, Shibata M A, Tsuda H, Wild C P, Montesano R, Fukushima S
First Department of Pathology, Nagoya City University Medical School.
Jpn J Cancer Res. 1993 Feb;84(2):139-46. doi: 10.1111/j.1349-7006.1993.tb02847.x.
The effects of aging on the multi-organ carcinogenesis induced in rats by N-methyl-N-nitrosourea (MNU), a direct carcinogen which does not need metabolic activation to exert carcinogenicity, were examined in male F344 rats. In the first experiment, rats at 6, 52, and 98 weeks of age were treated with MNU (20 mg/kg body weight, i.p.) twice weekly for 6 weeks and then maintained without any further treatment for 24 weeks in the case of young and middle-aged rats and for 18 weeks in the case of the old rats. In young rats, malignant lymphomas, particularly thymic types, were observed at significantly high incidence. A striking result in the middle-aged rats was the significantly higher incidence of adenocarcinomas in the small intestine than in young or old animals. The induction of proliferative and neoplastic lesions of the large intestine also tended to be increased in middle-aged rats. In addition, epithelial hyperplasia of the tongue, but not the forestomach, occurred at the highest incidence in the middle-aged group. There were no differences in the induction of epithelial lesions in the urinary bladder among the groups. In a second experiment, investigation of DNA synthesis in the tongue, small and large intestines, urinary bladder and lymph nodes did reveal significant increases or tendency for increase in the MNU-treated groups, but without differences with age. In contrast, the thymus of young rats showed significantly increased incorporation of BrdU label after administration of MNU, whereas it was markedly reduced in middle-aged rats. In a third experiment, O6-methyldeoxyguanine (O6-medG) DNA adduct formation was immunohistochemically detected in various organs including the thymus, forestomach, and small intestine without any differences with age. Thus, the results demonstrated that while the target organs of MNU are modified by the age of the animals, levels of DNA synthesis and O6-medG DNA adduct formation in most cases can not explain the observed differences in carcinogenic susceptibility.
研究了衰老对雄性F344大鼠多器官致癌作用的影响，该致癌作用由直接致癌物N-甲基-N-亚硝基脲（MNU）诱导，MNU无需代谢激活即可发挥致癌性。在第一个实验中，对6周龄、52周龄和98周龄的大鼠每周两次腹腔注射MNU（20mg/kg体重），持续6周。然后，年轻和中年大鼠在无进一步处理的情况下维持24周，老年大鼠维持18周。在年轻大鼠中，恶性淋巴瘤尤其是胸腺型淋巴瘤的发生率显著较高。中年大鼠的一个显著结果是小肠腺癌的发生率显著高于年轻或老年动物。中年大鼠大肠增殖性和肿瘤性病变的诱导也有增加的趋势。此外，舌上皮增生而非前胃上皮增生在中年组的发生率最高。各组膀胱上皮病变的诱导情况无差异。在第二个实验中，对舌、小肠、大肠、膀胱和淋巴结中的DNA合成进行研究，结果显示MNU处理组有显著增加或增加趋势，但与年龄无关。相反，年轻大鼠的胸腺在给予MNU后BrdU标记掺入显著增加，而中年大鼠则明显减少。在第三个实验中，通过免疫组织化学检测了包括胸腺、前胃和小肠在内的各种器官中O6-甲基脱氧鸟嘌呤（O6-medG）DNA加合物的形成，结果显示与年龄无关。因此，结果表明，虽然MNU的靶器官会因动物年龄而改变，但在大多数情况下，DNA合成水平和O6-medG DNA加合物的形成无法解释观察到的致癌易感性差异。
