Castonguay A, Rioux N
Laboratory of Cancer Etiology and Chemoprevention, School of Pharmacy, Laval University, Quebec City, Canada.
Carcinogenesis. 1997 Mar;18(3):491-6. doi: 10.1093/carcin/18.3.491.
The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent lung carcinogen in mice and is most likely involved in the aetiology of tobacco-induced lung cancer. Two protocols using NNK and A/J mice have been developed. In the single-dose protocol, each mouse was injected once with 2 mg of NNK. In the 7-week protocol, each mouse received 9.1 mg of NNK in drinking water during 7 weeks. Mice were killed 16 weeks after NNK treatment. We observed a near-Gaussian distribution in the number of tumours per mouse in the single protocol, but not in the 7-week protocol. In the 7-week protocol, a significant number (8.6%) of mice had more than 20 tumours/mouse. In the single-dose protocol, no mouse had more than 20 tumours. Sulindac at a dose of 123 mg/kg of diet inhibits lung tumourigenesis in the 7-week protocol, but not in the single-dose protocol. We observed that the inhibition of tumourigenesis in the 7-week protocol was proportional to the logarithm of the dose of sulindac between 15 and 123 mg/kg of diet. Treatment of mice for 7 weeks inhibits the primary humoral response to sheep red blood cells by 70%. This observation is particularly significant considering that NNK is present in tobacco smoke and that tobacco smoking suppresses both the specific and non-specific humoral and cellular immunity. Single injections of 2.0, 3.5 or 5.0 mg of NNK had no effect on this response. Our results suggest that the immunosuppressive effects of NNK contribute to its high carcinogenic potency particularly in sustained or life-time exposure models. We hypothesize that sulindac promotes the recovery of immune system from the NNK-mediated suppression observed in the 7-week protocol. This study illustrates the importance of selecting the most appropriate protocol of carcinogen treatment in investigating the efficacies of cancer chemopreventive agents.
烟草特异性亚硝胺4-(甲基亚硝胺基)-1-(3-吡啶基)-1-丁酮(NNK)是一种对小鼠有强致癌性的物质，很可能与烟草诱导的肺癌病因有关。已开发出两种使用NNK和A/J小鼠的实验方案。在单剂量方案中，每只小鼠注射一次2毫克NNK。在7周方案中，每只小鼠在7周内饮用含9.1毫克NNK的水。NNK处理16周后处死小鼠。我们观察到单剂量方案中每只小鼠的肿瘤数量呈近似高斯分布，但7周方案中并非如此。在7周方案中，相当数量(8.6%)的小鼠每只肿瘤超过20个。在单剂量方案中，没有小鼠的肿瘤超过20个。饮食中剂量为123毫克/千克的舒林酸在7周方案中可抑制肺肿瘤发生，但在单剂量方案中则无此作用。我们观察到，在7周方案中，肿瘤发生的抑制作用与饮食中舒林酸剂量在15至123毫克/千克之间的对数成正比。对小鼠进行7周治疗可使对绵羊红细胞的初次体液反应抑制70%。考虑到NNK存在于烟草烟雾中，且吸烟会抑制特异性和非特异性体液及细胞免疫，这一观察结果尤为重要。单次注射2.0、3.5或5.0毫克NNK对此反应无影响。我们的结果表明，NNK的免疫抑制作用尤其在持续或终生暴露模型中促成了其高致癌潜能。我们推测舒林酸可促进免疫系统从7周方案中观察到的NNK介导的抑制中恢复。本研究说明了在研究癌症化学预防剂的疗效时选择最合适的致癌物处理方案的重要性。
