Pepin P, Bouchard L, Nicole P, Castonguay A
Laboratory of Cancer Etiology and Chemoprevention, School of Pharmacy, Laval University, Quebec City, Canada.
Carcinogenesis. 1992 Mar;13(3):341-8. doi: 10.1093/carcin/13.3.341.
The efficacies of the non-steroidal, anti-inflammatory drug sulindac and the schistosomicidal agent oltipraz in inhibiting lung tumorigenesis was measured in A/J mice. Lung tumors (15.7 tumors/mouse) were induced by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK; 9.1 mg/mouse) administered in drinking water for 7 weeks. Feeding mice with sulindac (123 mg/kg diet), 2 weeks before carcinogen treatment until they were killed reduced tumor multiplicity by 53%. Oltipraz (250 mg/kg diet), however, has no effect on tumorigenesis. The absorption and metabolism of NNK were compared in the stomachs and intestines isolated from mice fed AIN-76A diet or sulindac + diet. Sulindac had no effect on alpha-carbon hydroxylation, pyridine N-oxidation or carbonyl reduction of NNK. Mouse lung explants were cultured with 4.7 microM [5-3H]NNK for 4 or 8 h. The addition of 1 mM sulindac to the culture medium reduces the alpha-carbon hydroxylation and pyridine N-oxidation of NNK. However, the administration of sulindac in the diet prior to the excision of the lung explants had no effect on these two metabolic pathways. We compared the levels of sulindac and its sulfide and sulfone metabolites in the lungs, livers and plasma of mice fed an AIN-76A diet containing 130 mg sulindac/kg for 2 weeks. The sulfide metabolite was the most abundant of the three compounds in plasma (17.6 pmol/microliters) and liver tissues (17.7 pmol/mg) but it could not be detected in lung tissues. These results show that non-steroidal anti-inflammatory drugs constitute a new class of chemopreventive agents in lung tumorigenesis. The tumor chemopreventive activity of sulindac is not mediated by the sulfide metabolite responsible for its anti-inflammatory activity.
在A/J小鼠中测定了非甾体抗炎药舒林酸和杀血吸虫剂奥替普拉抑制肺癌发生的效果。通过在饮用水中给予烟草特异性亚硝胺4-(甲基亚硝胺基)-1-(3-吡啶基)-1-丁酮（NNK；9.1毫克/小鼠）7周来诱导肺癌（每只小鼠15.7个肿瘤）。在致癌物处理前2周给小鼠喂食舒林酸（123毫克/千克饮食）直至处死，可使肿瘤多重性降低53%。然而，奥替普拉（250毫克/千克饮食）对肿瘤发生没有影响。比较了从喂食AIN-76A饮食或舒林酸+饮食的小鼠分离的胃和肠道中NNK的吸收和代谢情况。舒林酸对NNK的α-碳羟基化、吡啶N-氧化或羰基还原没有影响。用4.7微摩尔[5-³H]NNK培养小鼠肺外植体4或8小时。向培养基中添加1毫摩尔舒林酸可降低NNK的α-碳羟基化和吡啶N-氧化。然而，在切除肺外植体之前在饮食中给予舒林酸对这两种代谢途径没有影响。我们比较了喂食含130毫克舒林酸/千克的AIN-76A饮食2周的小鼠的肺、肝和血浆中舒林酸及其硫化物和砜代谢物的水平。硫化物代谢物是血浆（17.6皮摩尔/微升）和肝组织（17.7皮摩尔/毫克）中这三种化合物中含量最丰富的，但在肺组织中未检测到。这些结果表明，非甾体抗炎药构成了肺癌发生中的一类新型化学预防剂。舒林酸的肿瘤化学预防活性不是由负责其抗炎活性的硫化物代谢物介导的。
