Rao Chinthalapally V, Reddy Bandaru S, Steele Vernon E, Wang C-X, Liu Xiaoping, Ouyang Nengtai, Patlolla Jagan M R, Simi Barbara, Kopelovich Levy, Rigas Basil
Department of Medicine, Hem-Onc Section, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Mol Cancer Ther. 2006 Jun;5(6):1530-8. doi: 10.1158/1535-7163.MCT-06-0061.
Nitric oxide-releasing nonsteroidal anti-inflammatory drugs (NO-NSAID) are promising chemoprevention agents; unlike conventional NSAIDs, they seem free of appreciable adverse effects, while they retain beneficial activities of their parent compounds. Their effect on colon carcinogenesis using carcinoma formation as an end point is unknown. We assessed the chemopreventive properties of NO-indomethacin (NCX 530) and NO-aspirin (NCX 4016) against azoxymethane-induced colon cancer. Seven-week-old male F344 rats were fed control diet, and 1 week later, rats received two weekly s.c. injections of azoxymethane (15 mg/kg body weight). Two weeks after azoxymethane treatment, rats (48 per group) were fed experimental diets containing NO-indomethacin (0, 40, or 80 ppm), or NO-aspirin (1,500 or 3,000 ppm), representing 40% and 80% of the maximum tolerated dose. All rats were killed 48 weeks after azoxymethane treatment and assessed for colon tumor efficacy and molecular changes in colonic tumors and normally appearing colonic mucosa of different dietary groups. Our results suggest that NO-indomethacin at 40 and 80 ppm and NO-aspirin at 3,000 ppm significantly suppressed both tumor incidence (P < 0.01) and multiplicity (P < 0.001). The degree of inhibition was more pronounced with NO-indomethacin at both dose levels (72% and 76% inhibition) than with NO-aspirin (43% and 67%). NO-indomethacin at 40 and 80 ppm and NO-aspirin at 3,000 ppm significantly inhibited the colon tumors' (P < 0.01 to P < 0.001) total cyclooxygenase (COX), including COX-2 activity (52-75% inhibition) and formation of prostaglandin E2 (PGE2), PGF2alpha, and 6-keto-PGF1alpha, and TxB2 from arachidonic acid (53-77% inhibition). Nitric oxide synthase 2 (NOS-2) activity and beta-catenin expression were suppressed in animals given NO-NSAID. In colonic crypts and tumors of animals fed these two NO-NSAIDs, there was a significant decrease in proliferating cell nuclear antigen labeling when compared with animals fed the control diet. The results of this study provide strong evidence that NO-NSAIDs possess strong inhibitory effect against colon carcinogenesis; their effect is associated with suppression of COX and NOS-2 activities and beta-catenin levels in colon tumors. These results pave the way for the rational design of human clinical trials.
释放一氧化氮的非甾体抗炎药（NO-NSAID）是很有前景的化学预防剂；与传统的非甾体抗炎药不同，它们似乎没有明显的不良反应，同时保留了其母体化合物的有益活性。它们以癌形成作为终点对结肠癌发生的影响尚不清楚。我们评估了NO-吲哚美辛（NCX 530）和NO-阿司匹林（NCX 4016）对氧化偶氮甲烷诱导的结肠癌的化学预防特性。7周龄雄性F344大鼠喂食对照饮食，1周后，大鼠每周皮下注射两次氧化偶氮甲烷（15mg/kg体重）。氧化偶氮甲烷处理两周后，大鼠（每组48只）喂食含NO-吲哚美辛（0、40或80ppm）或NO-阿司匹林（1500或3000ppm）的实验饮食，分别相当于最大耐受剂量的40%和80%。所有大鼠在氧化偶氮甲烷处理48周后处死，评估结肠肿瘤疗效以及不同饮食组结肠肿瘤和外观正常的结肠黏膜中的分子变化。我们的结果表明，40和80ppm的NO-吲哚美辛以及3000ppm的NO-阿司匹林均显著抑制肿瘤发生率（P<0.01）和肿瘤多发性（P<0.001）。在两个剂量水平上，NO-吲哚美辛的抑制程度（72%和76%抑制）比NO-阿司匹林（43%和67%）更明显。40和80ppm的NO-吲哚美辛以及3000ppm的NO-阿司匹林显著抑制结肠肿瘤的总环氧化酶（COX）（P<0.01至P<0.001），包括COX-2活性（52 - 75%抑制）以及花生四烯酸生成前列腺素E2（PGE2）、PGF2α、6-酮-PGF1α和TxB2（53 - 77%抑制）。给予NO-NSAID的动物中，一氧化氮合酶2（NOS-2）活性和β-连环蛋白表达受到抑制。与喂食对照饮食的动物相比，喂食这两种NO-NSAID的动物的结肠隐窝和肿瘤中增殖细胞核抗原标记显著减少。本研究结果提供了有力证据，表明NO-NSAIDs对结肠癌发生具有强大的抑制作用；它们的作用与结肠肿瘤中COX和NOS-2活性以及β-连环蛋白水平的抑制有关。这些结果为合理设计人类临床试验铺平了道路。
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