Moorghen M, Orde M, Finney K J, Appleton D R, Watson A J
Department of Pathology and Microbiology, University of Bristol, UK.
Cell Prolif. 1998 Apr;31(2):59-70. doi: 10.1046/j.1365-2184.1998.00111.x.
In a previous study we reported that the NSAID sulindac had a marked inhibitory effect on the development of colonic tumours in mice treated with the carcinogen 1,2-dimethylhydrazine (DMH). In this study we examined the effects of sulindac in respect of cell-kinetic changes in mouse colonic mucosa as determined by flash labelling with the thymidine analogue bromodeoxyuridine (BrdUrd) at varying intervals during the process of colonic carcinogenesis. We also investigated the possibility that these changes may be modulated by misoprostol a prostaglandin E1 analogue. Four groups of 36 mice each were treated for 18 weeks with the following drug/s respectively: (1) DMH; (2) DMH and sulindac; (3) DMH, sulindac and misoprostol; and (4) DMH and misoprostol. Three animals from each group were killed each week between the sixth week and the eighteenth week after the start of the experiment. A 1-h flash label technique was employed and paraffin sections of colonic mucosa were examined. For each animal a total of 50 perfect axially cut crypts were chosen and the following parameters determined: crypt length, labelling index and labelling index distribution: the data were analysed using the computer program GLIM. For each of the four groups, crypt lengths increased significantly with the duration of treatment with no significant difference between the groups. In sulindac-treated animals the labelling index for all positions increased with duration of treatment whereas for animals not treated with sulindac there was no significant difference in labelling index with respect to duration of treatment. The administration of misoprostol did not appear to significantly alter the effects of sulindac. It is postulated that the observed increase in cell proliferation could be a compensatory phenomenon occurring secondary to loss of crypt epithelial cells by apoptosis induced by sulindac. Also the finding of an increase in labelling index mediated by a chemopreventive agent indirectly questions the rationale behind the therapeutic manipulation of crypt cell proliferation in order to reduce the risk of colon cancer.
在之前的一项研究中，我们报告称，非甾体抗炎药舒林酸对用致癌物1,2 - 二甲基肼（DMH）处理的小鼠结肠肿瘤的发生具有显著的抑制作用。在本研究中，我们通过在结肠癌变过程中的不同时间间隔用胸苷类似物溴脱氧尿苷（BrdUrd）进行快速标记，来检测舒林酸对小鼠结肠黏膜细胞动力学变化的影响。我们还研究了这些变化是否可能被米索前列醇（一种前列腺素E1类似物）所调节。四组小鼠，每组36只，分别用以下药物治疗18周：（1）DMH；（2）DMH和舒林酸；（3）DMH、舒林酸和米索前列醇；（4）DMH和米索前列醇。在实验开始后的第6周和第18周之间，每组每周处死3只动物。采用1小时快速标记技术，并检查结肠黏膜的石蜡切片。对于每只动物，总共选择50个完美的轴向切割隐窝，并确定以下参数：隐窝长度、标记指数和标记指数分布：数据使用计算机程序GLIM进行分析。对于四组中的每一组，隐窝长度均随着治疗时间的延长而显著增加，各组之间无显著差异。在接受舒林酸治疗的动物中，所有位置的标记指数均随着治疗时间的延长而增加，而对于未接受舒林酸治疗的动物，标记指数在治疗时间方面无显著差异。米索前列醇的给药似乎并未显著改变舒林酸的作用。据推测，观察到的细胞增殖增加可能是舒林酸诱导的凋亡导致隐窝上皮细胞丢失后发生的一种代偿现象。此外，化学预防剂介导的标记指数增加这一发现间接质疑了为降低结肠癌风险而对隐窝细胞增殖进行治疗性操作的基本原理。
