Hisamuddin Irfan M, Wehbi Mohammad A, Schmotzer Brian, Easley Kirk A, Hylind Linda M, Giardiello Francis M, Yang Vincent W
Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, 201 Whitehead Research Building, 615 Michael Street, Atlanta, GA 30322, USA.
Cancer Epidemiol Biomarkers Prev. 2005 Oct;14(10):2366-9. doi: 10.1158/1055-9965.EPI-05-0312.
Sulindac is a nonsteroidal antiinflammatory drug with a chemopreventive effect in patients with familial adenomatous polyposis (FAP). In vivo, the active form of sulindac is sulindac sulfide, which is inactivated by the hepatic microsomal enzyme, flavin monooxygenase 3 (FMO3). In humans, numerous polymorphisms exist in FMO3, which alter enzymatic activity and subsequent substrate metabolism. We recently showed that certain polymorphic forms of FMO3 with reduced activity were associated with a more favorable response to sulindac in preventing the formation of adenomas in patients with FAP without polyps at baseline. Here, we determined whether these FMO3 polymorphisms correlated with the ability of sulindac to regress polyposis in patients with FAP who had polyps prior to treatment. Nineteen patients were treated with 150 mg sulindac twice a day for 6 months. The size and number of polyps in each patient was assessed at baseline (prior to the administration of sulindac), and at 3 and 6 months. Genotyping was done on seven established FMO3 polymorphisms with functional significance-M66I, E158K, P153L, V257M, E305X, E308G, and R492W. Statistical analyses were done with Wilcoxon rank sum test. Of the loci examined, only E158K and E308G showed polymorphic changes. Six patients exhibited polymorphisms in both E158K and E308G loci and were designated as genotype combination 1. The remaining patients were designated as genotype combination 2. Over the course of treatment, patients with genotype combination 1 had a greater reduction in both the size and number of polyps than those with genotype combination 2. These results suggest that combined polymorphic changes in the E158K and E308G alleles may protect against polyposis in patients with FAP treated with sulindac.
舒林酸是一种对家族性腺瘤性息肉病（FAP）患者具有化学预防作用的非甾体抗炎药。在体内，舒林酸的活性形式是舒林酸硫化物，它会被肝脏微粒体酶黄素单加氧酶3（FMO3）灭活。在人类中，FMO3存在众多多态性，这些多态性会改变酶活性及随后的底物代谢。我们最近发现，某些活性降低的FMO3多态性形式与舒林酸在预防基线时无息肉的FAP患者腺瘤形成方面的更有利反应相关。在此，我们确定这些FMO3多态性是否与舒林酸使治疗前有息肉的FAP患者息肉病消退的能力相关。19名患者每天两次服用150毫克舒林酸，持续6个月。在基线（舒林酸给药前）、3个月和6个月时评估每位患者息肉的大小和数量。对具有功能意义的7种已确定的FMO3多态性进行基因分型——M66I、E158K、P153L、V257M、E305X、E308G和R492W。采用Wilcoxon秩和检验进行统计分析。在所检测的基因座中，只有E158K和E308G显示出多态性变化。6名患者在E158K和E308G基因座均表现出多态性，被指定为基因型组合1。其余患者被指定为基因型组合2。在治疗过程中，基因型组合1的患者息肉的大小和数量减少幅度均大于基因型组合2的患者。这些结果表明，E158K和E308G等位基因的联合多态性变化可能对接受舒林酸治疗的FAP患者的息肉病具有保护作用。
