Inhibition of rat colon tumors by sulindac and sulindac sulfone is independent of K-ras (codon 12) mutation
Inhibition of rat colon tumors by sulindac and sulindac sulfone is independent of K-ras (codon 12) mutation
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DOI：
10.1152/ajpgi.2000.278.2.g266
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发表时间：
2000-02-01
影响因子：
4.5
通讯作者：
O'Brien, PE
中科院分区：
文献类型：
--
作者：
De Jong, TA;Skinner, SA;O'Brien, PE
使用非甾体抗炎药（NSAID）可将结直肠癌的风险降低40- 50%。先前的研究表明，NSAID对结直肠癌的有效抑制可能取决于K-ras突变的存在或不存在。本研究旨在确定舒林酸和舒林酸砜对结直肠癌的抑制作用与1，2-二甲基肼二盐酸盐大鼠模型中存在活化K-ras突变之间的关系。从肿瘤诱导后20周开始，对雄性Sprague-Dawley大鼠经口给予舒林酸（20 mg.kg（-1）. day（-1））、舒林酸砜（40 mg. kg（-1）.day（-1））或溶媒，持续4周。在治疗前通过剖腹手术和结肠镜测量肿瘤数量和体积，并在治疗后再次测量。与对照组大鼠相比，舒林酸和舒林酸砜治疗显著减少了结肠直肠肿瘤的数量和体积。对于K-ras（密码子12）突变检测，在终点收集冷冻肿瘤组织。我们在21例对照肿瘤中发现11例（52%）K-ras密码子12突变。舒林酸治疗组中K-ras突变的肿瘤比例[5/8（62%）;比值比= 1.51（95%置信区间= 0.29，8.33）]和舒林酸砜治疗肿瘤的比例[9/14（64%）;比值比= 1.63（95%置信区间= 0.41，6.66）]与对照组无显著差异。抑瘤作用与K-ras（密码子12）突变状态无关，提示舒林酸和舒林酸砜抑制大鼠大肠癌的机制与K-ras突变无关。
Nonsteroidal anti-inflammatory drug (NSAID) use reduces the risk of colorectal cancer by 40-50%. Previous studies suggest that effective inhibition of colorectal cancer by NSAIDs may be dependent on the presence or absence of a K-ras mutation. This study was aimed at determining the relationship between inhibition of colorectal cancer by sulindac and sulindac sulfone and the presence of activating K-ras mutations in the 1,2-dimethylhydrazine dihydrochloride rat model. Sulindac (20 mg.kg(-1).day(-1)), sulindac sulfone (40 mg.kg(-1).day(-1)), or vehicle was administered orally to male Sprague-Dawley rats for a 4-wk period beginning 20 wk after tumor induction. Tumor number and volume were measured before treatment by laparotomy and colonoscopy and again after treatment. Sulindac and sulindac sulfone treatment significantly reduced the number and volume of colorectal tumors compared with control rats. For K-ras (codon 12) mutation detection, frozen tumor tissue was collected at the endpoint. We found K-ras codon 12 mutations in 11 of 21 (52%) control tumors. The proportion of tumors with K-ras mutations in the sulindac-treated group [5 of 8 (62%); odds ratio = 1.51 (95% confidence interval = 0.29, 8.33)] and the proportion of sulindac sulfone-treated tumors [9 of 14 (64%); odds ratio = 1.63 (95% confidence interval = 0.41, 6.66)] were not significantly different from controls. Tumor inhibition did not correlate with K-ras (codon 12) mutation status, which suggests that the mechanism of inhibition of rat colorectal cancer by sulindac and sulindac sulfone is independent of K-ras mutation.