Flinders Ctr. for Cancer Prevention and Control, Flinders Univ., South Australia, 5042.
Am J Physiol Gastrointest Liver Physiol. 2010 Jun;298(6):G860-4. doi: 10.1152/ajpgi.00330.2009. Epub 2010 Mar 25.
Toxicity and gastrointestinal side effects limits the use of nonsteroidal anti-inflammatory drugs (NSAIDs) as agents to prevent colorectal cancer. These undesirable effects appear to be related to the inhibition of cyclooxygenase-associated pathways. Using the azoxymethane (AOM)-rat model of carcinogenesis, we aimed to test the potency of a low-toxicity R-flurbiprofen and whether NSAIDs have differing effects on regional tumor subtypes. Groups of 50 rats were gavaged 6 days a week with drug. After 1 and 2 wk on drug, rats were given intraperitoneal injection of AOM (15 mg/kg body wt). Groups were controls, sulindac (nonselective cyclooxygenase inhibitor) 5 and 20 mg/kg body wt per day, and R-flurbiprofen 30 mg/kg body wt per day. Tumor location, size, and histological subtype (either mucinous or nonmucinous) were recorded after 30 wk. The incidence of colon tumors was significantly reduced in the sulindac 20 mg (P < 0.001) and the R-flurbiprofen groups (P < 0.03) compared with the control group. The sulindac 20 mg and R-flurbiprofen groups also showed a reduced number of distal colon tumors (P < 0.03), whereas proximal tumors were not affected. Tumors only of the nonmucinous subtype were significantly reduced with the sulindac 20 mg and R-flurbiprofen groups (P < 0.001). Tumor size was not significantly different between all groups. Only the sulindac 20 mg group showed a reduced colonic prostaglandin E2 concentration. The sulindac groups showed a dose-dependant reduction in body weight gain (P < 0.001). In conclusion, R-flurbiprofen at a dose of 30 mg/kg body wt per day was well tolerated by the animals and, along with sulindac at 30 mg/day body wt, showed protection against the development of colon cancer in the rat-AOM model.
毒性和胃肠道副作用限制了非甾体抗炎药（NSAIDs）作为预防结直肠癌的药物的使用。这些不良影响似乎与环氧化酶相关途径的抑制有关。使用氧化偶氮甲烷（AOM）-大鼠致癌模型，我们旨在测试低毒性 R-氟比洛芬的效力，以及 NSAIDs 是否对区域性肿瘤亚型有不同的作用。每组 50 只大鼠每周接受 6 天的药物灌胃。在药物治疗 1 和 2 周后，大鼠给予腹腔注射 AOM（15mg/kg 体重）。对照组、舒林酸（非选择性环氧化酶抑制剂）5 和 20mg/kg 体重/天以及 R-氟比洛芬 30mg/kg 体重/天。30 周后记录肿瘤位置、大小和组织学亚型（粘液性或非粘液性）。与对照组相比，舒林酸 20mg（P < 0.001）和 R-氟比洛芬组（P < 0.03）的结肠肿瘤发生率显著降低。舒林酸 20mg 和 R-氟比洛芬组还显示出远端结肠肿瘤数量减少（P < 0.03），而近端肿瘤不受影响。只有舒林酸 20mg 和 R-氟比洛芬组的非粘液性肿瘤显著减少（P < 0.001）。所有组之间的肿瘤大小没有显著差异。只有舒林酸 20mg 组的结肠前列腺素 E2 浓度降低。舒林酸组的体重增加呈剂量依赖性减少（P < 0.001）。总之，每天 30mg/kg 体重的 R-氟比洛芬被动物耐受良好，与每天 30mg/kg 体重的舒林酸一起，在大鼠 AOM 模型中显示出对结肠癌发展的保护作用。
