MNNG在大鼠胃癌前期病变造模中的量效关系

Dose-effect correlation of N-methyl-N'-nitro-Nnitrosoguanidine in inducing gastric precancerous lesions in rats

目的观察N-甲基-N'-硝基-N-亚硝基胍(N-methylN'-nitro-N-nitrosoguanidine,MNNG)不同的给药途径和剂量对SD大鼠胃癌前期病变造模中的胃黏膜组织的病理学影响.方法150只体质量80-100 g的SD♂大鼠随机分成6组,空白对照自由饮组,空白对照灌胃组,MNNG低浓度组,MNNG中浓度组,MNNG高浓度组,MNNG灌胃组,各组均为25只.低、中、高浓度组分别采用50、100、150冚g/mL的MNNG自由饮,3组联合使用高Na饮水(15%NaCl饮水)、饥饱失常、雷尼替丁加工饲料造模;灌胃组在低浓度组的基础上,每日以0.017 mol/L的MNNG溶液灌胃(根据不同时期体质量计算灌胃量).连续28 wk,比较各组大鼠的一般情况、组织病理学变化情况,并且运用免疫组织化学的方法,测定各组胃黏膜组织Bcl-2的表达.结果低浓度组大鼠,鳞状上皮改变较多,发生率为28%,仅炎性改变的为11例;中浓度组大鼠,萎缩肠化的发生率为65.2%,少数发生鳞状上皮改变;高浓度组大鼠发生萎缩、肠化、鳞状上皮化生以及癌变(鳞癌),其中癌变率为33.4%,诱变率为85.7%;灌胃组大鼠,在低浓度组的基础上,每日以0.017 mol/L的MNNG溶液灌胃(根据不同时期体质量计算灌胃量),发生萎缩、肠化、鳞状上皮化生以及癌变,诱变率为84.2%.免疫组织化学法检测Bcl-2,呈现与MNNG造型药物浓度相关的高表达.结论在MNNG的诱导下,联合饲喂雷尼替丁饲料、饥饱失常、高Na饮水、灌胃,可以成功诱导出大鼠萎缩、肠化、萎缩伴肠化的模型.

AIM To observe the pathological effect of different doses of N-methyl-N＇-nitro-N-nitrosoguanidine （MNNG） via different administration routes on rat gastric mucosa in inducing gastric precancerous lesions. METHODS A total of 150 SD male rats weighing 80-100 g were randomly and equally divided into six groups： A-F. Group A was given water, group B was gavaged with normal saline, groups C-E were given low-, medium- and high-dose MNNG in water （50, 100, and 150 μg/mL） and fed a diet containing ranitidine, and group F was gavaged with 0.017 mol/L MNNG on the basis of the regimen for group C. After 28 wk, general situation and histopathological changes were compared between each group. Immunohistochemical method was used to detect the expression of Bcl-2 in gastric mucosal tissue. In the low-dose group, 28% of rats developed squamous epithelial changes and 11 rats showed only inflammatory changes. In the medium-dose group, 65.2% of rats developed atrophy and intestinal metaplasia, and only a few rats showed changes in the squamous epithelium. Rats in the high-dose group developed atrophy, intestinal metaplasia, squamous metaplasia, and canceration （squamous cell carcinoma）, with a canceration rate of 33.4% and induction rate of 85.7%. Rats in the MNNG gavage group developed atrophy, intestinal metaplasia, squamous metaplasia and canceration, demonstrating an induction rate of 84.2%. MNNG up-regulated Bcl-2 expression in gastric mucosal tissue in a dose-dependent manner. CONCLUSION Atrophy, intestinal metaplasia, and atrophy with intestinal metaplasia could be successfully induced with MNNG combined with other treatments. A relatively higher induction rate was observed in the high-dose MNNG group and MNNG gavage group.