5-Aminosalicylic acid inhibits colitis-associated but not sporadic colorectal neoplasia in a novel conditional Apc mouse model
5-Aminosalicylic acid inhibits colitis-associated but not sporadic colorectal neoplasia in a novel conditional Apc mouse model
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DOI：
10.1093/carcin/bgp113
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发表时间：
2009-07-01
期刊：
影响因子：
4.7
通讯作者：
Verspaget, Hein W.
中科院分区：
文献类型：
--
作者：
Koelink, Pim J.;Robanus-Maandag, Els C.;Verspaget, Hein W.
遗传易感性、生活习惯和炎症性肠病(IBD)相关性结肠炎是结直肠癌的主要危险因素。5-氨基水杨酸(5-ASA，美沙拉秦)是IBD的主要治疗方法，被认为可以降低发生结直肠癌的风险。我们的目标是确定5-ASA灌肠抑制小鼠散发性和结肠炎相关肿瘤发展的能力。APC(15lox/+)小鼠自发发展为散发性结直肠癌，在5周龄时用5-ASA或安慰剂灌肠治疗3周，并在8周龄时检查结直肠癌的发生情况。通过在诱导结肠炎期间和/或在诱导结肠炎期间和/或之后联合使用5-ASA或安慰剂灌肠，通过给予葡聚糖硫酸钠、诱导肠道炎症和加速结直肠肿瘤发生来研究这些小鼠结肠炎相关肿瘤的发展。5-ASA可显著降低大肠远端结肠炎加速的肿瘤发展50%，从19.4+/-2.7降至9.4+/-2.4(平均肿瘤数+/-扫描电子显微镜，P=0.02)。5-ASA仅在肠道炎症期间和/或之后给药时有效。然而，5-ASA不能减少FabplCre；APC(15lox/+)小鼠的散发性肿瘤发展。5-ASA有抑制结肠炎相关性结直肠癌上皮细胞增殖的趋势，但在散发性结直肠癌中无此作用。总之，在炎症诱导期间和/或之后给药时，5-ASA药物可抑制FabplCre；APC(15lox/+)小鼠结肠炎相关肿瘤的发展。然而，在这种小鼠模型中，5-ASA并不能减少散发性肿瘤的发展。
Genetic predisposition, life-style habits and inflammatory bowel diseases (IBD)-related colitis are a main risk factor for colorectal cancer (CRC). 5-Aminosalicylic acid (5-ASA, mesalazine) is a mainstay therapy in IBD and believed to reduce the risk for developing CRC. We aimed to determine the ability of 5-ASA enemas to inhibit the development of sporadic and colitis-related neoplasia in mice. FabplCre;Apc(15lox/+) mice, which spontaneously develop sporadic colorectal tumours, were treated at 5 weeks of age with 5-ASA or placebo enemas for 3 weeks and examined for colorectal tumourigenesis at 8 weeks of age. Colitis-related tumour development was investigated in these mice by administration of dextran sodium sulphate, inducing intestinal inflammation and accelerating colorectal tumourigenesis, combined with treatment of 5-ASA or placebo enemas during and/or after colitis induction. 5-ASA significantly reduced colitis-accelerated neoplasia development by 50%, from 19.4 +/- 2.7 to 9.4 +/- 2.4 (mean tumour numbers +/- SEM, P = 0.02), in the distal part of the large intestine covered by the enema. 5-ASA was only effective when given during and/or after the intestinal inflammatory period. 5-ASA did not reduce, however, sporadic neoplasia development in the FabplCre;Apc(15lox/+) mice. 5-ASA tended to reduce proliferation of epithelial cells in the colitis-associated colorectal tumours but not in the sporadic colorectal tumours. In conclusion, 5-ASA medication inhibits the development of colitis-associated tumours in FabplCre;Apc(15lox/+) mice when administered during and/or after the induction of inflammation. 5-ASA does not reduce, however, sporadic tumour development in this mouse model.