Hagos Ghenet K, Carroll Robert E, Kouznetsova Tatiana, Li Qian, Toader Violeta, Fernandez Patricia A, Swanson Steven M, Thatcher Gregory R J
Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 S Wood Street, Chicago, IL 60612, USA.
Mol Cancer Ther. 2007 Aug;6(8):2230-9. doi: 10.1158/1535-7163.MCT-07-0069.
Chemopreventive agents in colorectal cancer possess either antiproliferative or anti-inflammatory actions. Nonsteroidal anti-inflammatory drugs (NSAID) and cyclooxygenase-2 inhibitors have shown promise, but are compromised by side effects. Nitric oxide donor NSAIDs are organic nitrates conjugated via a labile linker to an NSAID, originally designed for use in pain relief, that have shown efficacy in colorectal cancer chemoprevention. The NO chimera, GT-094, is a novel nitrate containing an NSAID and disulfide pharmacophores, a lead compound for the design of agents specifically for colorectal cancer. GT-094 is the first nitrate reported to reduce aberrant crypt foci (by 45%) when administered after carcinogen in the standard azoxymethane rat model of colorectal cancer. Analysis of proximal and distal colon tissue from 8- and 28-week rat/azoxymethane studies showed that GT-094 treatment reduced colon crypt proliferation by 30% to 69%, reduced inducible NO synthase (iNOS) levels by 33% to 67%, reduced poly(ADP-ribose)polymerase-1 expression and cleavage 2- to 4-fold, and elevated levels of p27 in the distal colon 3-fold. Studies in cancer cell cultures recapitulated actions of GT-094: antiproliferative activity and transient G(2)-M phase cell cycle block were measured in Caco-2 cells; apoptotic activity was examined but not observed; anti-inflammatory activity was seen in the inhibition of up-regulation of iNOS and endogenous NO production in lipopolysaccharide (LPS)-induced RAW 264.7 cells. In summary, antiproliferative, anti-inflammatory, and cytoprotective activity observed in vivo and in vitro support GT-094 as a lead compound for the design of NO chimeras for colorectal cancer chemoprevention.
结直肠癌的化学预防剂具有抗增殖或抗炎作用。非甾体抗炎药（NSAID）和环氧合酶-2抑制剂已显示出前景，但受到副作用的影响。一氧化氮供体NSAIDs是通过不稳定连接子与NSAID共轭的有机硝酸盐，最初设计用于缓解疼痛，已显示出在结直肠癌化学预防中的功效。NO嵌合体GT-094是一种新型硝酸盐，含有NSAID和二硫键药效基团，是设计专门用于结直肠癌药物的先导化合物。GT-094是在标准的结直肠癌偶氮甲烷大鼠模型中，在致癌物给药后给予时，首个被报道可减少异常隐窝灶（减少45%）的硝酸盐。对8周和28周大鼠/偶氮甲烷研究中的近端和远端结肠组织分析表明，GT-094治疗可使结肠隐窝增殖减少30%至69%，诱导型一氧化氮合酶（iNOS）水平降低33%至67%，聚（ADP-核糖）聚合酶-1表达和裂解减少2至4倍，并且使远端结肠中p27水平升高3倍。癌细胞培养研究重现了GT-094的作用：在Caco-2细胞中检测到抗增殖活性和短暂的G(2)-M期细胞周期阻滞；检查了凋亡活性但未观察到；在脂多糖（LPS）诱导的RAW 264.7细胞中，通过抑制iNOS上调和内源性NO产生观察到抗炎活性。总之，体内和体外观察到的抗增殖、抗炎和细胞保护活性支持GT-094作为设计用于结直肠癌化学预防的NO嵌合体的先导化合物。
