The sulfide metabolite of sulindac prevents tumors and restores enterocyte apoptosis in a murine model of familial adenomatous polyposis
The sulfide metabolite of sulindac prevents tumors and restores enterocyte apoptosis in a murine model of familial adenomatous polyposis
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DOI：
10.1093/carcin/19.1.87
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发表时间：
1998-01-01
期刊：
影响因子：
4.7
通讯作者：
Bertagnolli, MM
中科院分区：
文献类型：
--
作者：
Mahmoud, NN;Boolbol, SK;Bertagnolli, MM
舒林酸是一种非甾体抗炎药（NSAID），可有效治疗患有家族性腺瘤性息肉病（FAP）的人类肠腺瘤，并可有效预防C57 Bl/6 J-Min+（Min）小鼠（FAP动物模型）的肠肿瘤。舒林酸是一种前体药物，经肝脏和肠道植物群代谢为砜和硫醚，前者无抗炎活性，后者为活性抗炎代谢产物。在本研究中，我们确定了这些代谢产物中的哪一种负责舒林酸在Min小鼠中的抗肿瘤作用。Min小鼠用舒林酸砜或舒林酸硫醚处理（0.5 +/-0.1mg/天），Min小鼠和缺乏Ape突变（+/+）的纯合C57 B1/6 J- +/+正常同窝小鼠用作对照。在110日龄时，将所有小鼠安乐死并检查它们的肠道，对照Min小鼠每只小鼠有33.2 +/- 6.6个肿瘤，而舒林酸硫化物处理的Min小鼠有0.6 +/- 0.3个肿瘤（P < 0.001）和21.9 +/-4.5肿瘤/小鼠舒林砜治疗的Min小鼠（P > 0.05），Rlin对照小鼠和舒林酸砜处理的Min小鼠中观察到肠细胞凋亡减少，舒林酸硫化物使Min动物粘膜中的细胞凋亡水平恢复到正常水平，并使处理的Min动物小肠中的PGE（2）水平降低59%。这些数据表明舒林酸在APC缺陷动物中的抗肿瘤作用是由硫化物代谢物介导的，并且与组织前列腺素合成的抑制相关。
Sulindac, a non-steroidal anti-inflammatory drug (NSAID), is effective in treating intestinal adenomas in humans with Familial Adenomatous Polyposis (FAP) and in preventing intestinal tumors in the C57Bl/6J-Min + (Min) mouse, an animal model of FAP. Sulindac is a prodrug metabolized by the liver and intestinal flora to a sulfone, which has no anti-inflammatory activity, and a sulfide, which is the active anti-inflammatory metabolite, In this study, we determined which of these metabolites is responsible for the anti-tumor effect of sulindac in Min mice, Min mice were treated with either sulindac sulfone or sulindac sulfide (0.5 +/- 0.1 mg/day), Min mice and homozygous C57Bl/6J- +/+ normal litter-mates lacking the Ape mutation (+/+) were used as controls, At 110 days of age, all mice were euthanized and their intestinal tracts examined, Control Min mice had 33.2 +/- 6.6 tumors per mouse compared to 0.6 +/- 0.3 tumors for sulindac sulfide-treated Min mice (P < 0.001) and 21.9 +/- 4.5 tumors per mouse for sulindac sulfone-treated Min mice (P > 0.05), Decreased enterocyte apoptosis was observed in Rlin control mice and Min mice treated with sulindac sulfone, Sulindac sulfide restored to normal the level of apoptosis in the mucosa of Min animals and decreased levels of PGE(2) in the small intestine of treated Min animals by 59% (P < 0.001), These data suggest that the anti-tumor effect of sulindac in Apc-deficient animals is mediated by the sulfide metabolite and correlates with suppression of tissue prostaglandin synthesis.