Rioux N, Castonguay A
Laboratory of Cancer Etiology and Chemoprevention, Faculty of Pharmacy, Laval University, Quebec City, Canada.
Cancer Res. 1998 Dec 1;58(23):5354-60.
Acetylsalicylic acid (ASA) is known to prevent cancer development, but its mechanism of action remains unclear. In this study, we compared the efficacies of this nonspecific cyclooxygenase (COX) inhibitor with N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide (NS-398), a specific COX-2 inhibitor. COX-2-specific inhibitors are less toxic than ASA. Lung tumorigenesis was induced in A/J mice by the administration of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in the drinking water for 7 weeks (weeks 0 to +7). Groups of 25 A/J mice were fed ASA (588, 294, 147, or 73 mg/kg diet) before and throughout the assay (weeks -2 to +23). ASA at a dose of 588 mg/kg diet was the most effective because it reduced lung tumor multiplicity by 53%. The preventive effect of ASA increased with the dose, being of 32, 30, and 44% for 73, 147, and 294 mg/kg diet, respectively. NNK increased plasma prostaglandin E2 (PGE2) basal levels by 413%, whereas ASA attenuated this elevation in a dose-response manner (r2 = 0.99). Plasma PGE2 levels in ASA + NNK-treated mice correlate with the logarithm of the number of tumors (r2 = 0.99). NS-398 inhibited lung tumor multiplicity by 34% and returned plasma PGE2 to basal levels observed in untreated mice. Among the NNK-exposed mice, ASA and NS-398 treatment decreased the mean of the lung tumor volumes. Incubation of 82-132 and LM2 murine lung tumor cells with ASA or NS-398 decreased cell proliferation by 50% at concentrations higher than 100 microM. Incubations of NNK with COX-1 and -2 produced both activation and detoxification products by alpha-carbon hydroxylation and N-oxydation pathways, respectively. Bioactivation of NNK was more extensive by COX-2 than COX-1. Anti-COX-1 and -2, arachidonic acid, ASA, and NS-398 inhibited NNK bioactivation by COX-1 and -2 from 22-49%. Our data suggest that NNK is bioactivated by COX-2 in lung tissues and that COX-2-specific inhibitors might be promising chemopreventive agents.
已知乙酰水杨酸（ASA）可预防癌症发展，但其作用机制仍不清楚。在本研究中，我们比较了这种非特异性环氧化酶（COX）抑制剂与特异性COX-2抑制剂N-[2-(环己氧基)-4-硝基苯基]-甲磺酰胺（NS-398）的疗效。COX-2特异性抑制剂的毒性低于ASA。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）7周（第0至+7周），诱导A/J小鼠发生肺肿瘤。在实验前及整个实验过程中（第-2至+23周），给25只A/J小鼠组成的每组喂食ASA（588、294、147或73mg/kg饮食）。剂量为588mg/kg饮食的ASA最有效，因为它使肺肿瘤数量减少了53%。ASA的预防效果随剂量增加而增强，73、147和294mg/kg饮食的预防效果分别为32%、30%和44%。NNK使血浆前列腺素E2（PGE2）基础水平升高413%，而ASA以剂量反应方式减弱了这种升高（r2 = 0.99）。ASA + NNK处理小鼠的血浆PGE2水平与肿瘤数量的对数相关（r2 = 0.99）。NS-398使肺肿瘤数量减少34%，并使血浆PGE2恢复到未处理小鼠的基础水平。在暴露于NNK的小鼠中，ASA和NS-398处理降低了肺肿瘤体积的平均值。在浓度高于100μM时，用ASA或NS-398孵育82-132和LM2小鼠肺肿瘤细胞可使细胞增殖减少50%。NNK与COX-1和-2孵育分别通过α-碳羟基化和N-氧化途径产生活化产物和解毒产物。COX-2对NNK的生物活化作用比COX-1更广泛。抗COX-1和-2、花生四烯酸、ASA和NS-398可使COX-1和-2对NNK的生物活化作用抑制22%-49%。我们的数据表明，NNK在肺组织中被COX-2生物活化，且COX-2特异性抑制剂可能是有前景的化学预防剂。
