Siglin J C, Morse M A, Schut H A, Geil R G, Conran P B, Stoner G D
Department of Pathology, Medical College of Ohio, Toledo 43699-0008, USA.
Carcinogenesis. 1996 May;17(5):1135-40. doi: 10.1093/carcin/17.5.1135.
In this study we investigated the time course of O6-methylguanine (O6-meGua) levels and concomitant histopathological effects in the rat esophagus and liver following single and repeated s.c. administration of the esophagus-specific carcinogen N-nitrosomethylbenzylamine (NMBA). The primary purpose of this study was to determine if differences in the induction and/or persistence of O6-meGua might account for differences in the tumorigenicity of NMBA observed with treatment regimens of 0.5 mg/kg/dose, 3 doses/week for 5 weeks (a proven tumorigenic regimen) and 1.67 mg/kg/dose, 3 doses/week for 2 weeks (an essentially non-tumorigenic regimen). Results of the single dose experiment indicated that enzymatic activation of NMBA in the rat esophagus was not dose limited, at least at doses up to and including 5.0 mg/kg. Results of the repeated dose experiment demonstrated that the non-tumorigenic NMBA regimen produced significantly higher levels of esophageal O6-meGua compared with the tumorigenic NMBA regimen. During the 2 week treatment period of the non-tumorigenic regimen esophageal O6-meGua levels decreased progressively, but remained significantly higher than in the tumorigenic regimen. In contrast, the relatively lower O6-meGua levels of the tumorigenic regimen remained essentially unchanged during the course of treatment. At 72 h following conclusion of dosing no O6-meGua was detected in the esophagi of rats treated with either regimen. Microscopic examinations revealed that the non-tumorigenic NMBA regimen produced a marked cytotoxic effect on the esophageal epithelium, while microscopic esophageal changes observed with the tumorigenic regimen were generally less severe. In the liver O6-meGua was detected in only a few rats and no remarkable microscopic pathology was observed in this organ. Together these findings indicate that: (i) abbreviated NMBA treatment induces tumors in the rat esophagus only at levels that induce DNA damage without causing extensive cytotoxicity; (ii) the lack of NMBA tumorigenicity in the rat liver may be due, at least in part, to the rapid and efficient repair of O6-meGua adducts, coupled with the lack of necrosis and compensatory cell division in this organ.
在本研究中，我们调查了大鼠经皮下单次和重复给予食管特异性致癌物N-亚硝基甲基苄胺（NMBA）后，食管和肝脏中O6-甲基鸟嘌呤（O6-meGua）水平的时间进程以及伴随的组织病理学效应。本研究的主要目的是确定O6-meGua诱导和/或持续存在的差异是否可以解释用0.5 mg/kg/剂量、每周3次、共5周（一种已证实的致瘤方案）和1.67 mg/kg/剂量、每周3次、共2周（一种基本无致瘤性的方案）的治疗方案观察到的NMBA致瘤性差异。单次剂量实验结果表明，大鼠食管中NMBA的酶促活化不受剂量限制，至少在高达和包括5.0 mg/kg的剂量下如此。重复剂量实验结果表明，与致瘤性NMBA方案相比，无致瘤性NMBA方案产生的食管O6-meGua水平显著更高。在无致瘤性方案的2周治疗期内，食管O6-meGua水平逐渐下降，但仍显著高于致瘤性方案。相反，致瘤性方案中相对较低的O6-meGua水平在治疗过程中基本保持不变。给药结束后72小时，两种方案治疗的大鼠食管中均未检测到O6-meGua。显微镜检查显示，无致瘤性NMBA方案对食管上皮产生了明显的细胞毒性作用，而致瘤性方案观察到的食管微观变化通常较轻。在肝脏中，仅在少数大鼠中检测到O6-meGua，且该器官未观察到明显的微观病理学变化。这些发现共同表明：（i）缩短的NMBA治疗仅在诱导DNA损伤而不引起广泛细胞毒性的水平下诱导大鼠食管肿瘤；（ii）大鼠肝脏中NMBA无致瘤性可能至少部分归因于O6-meGua加合物的快速有效修复，以及该器官缺乏坏死和代偿性细胞分裂。
