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首页> 外文期刊>Molecular cancer therapeutics >Therapeutic effect of CS-706, a specific cyclooxygenase-2 inhibitor, on gallbladder carcinoma in BK5.ErbB-2 mice.
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Therapeutic effect of CS-706, a specific cyclooxygenase-2 inhibitor, on gallbladder carcinoma in BK5.ErbB-2 mice.

机译：CS-706，一种特定的环氧合酶2抑制剂，对BK5.ErbB-2小鼠胆囊癌的治疗作用。

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摘要

Biliary tract cancer is still challenging to treat and manage due to its poor sensitivity to conventional therapies and the inability to prevent or detect the early tumor formation. The most well known risk factor for gallbladder cancer is the presence of chronic inflammation, usually related to gallstones. It has been suggested that cyclooxygenase-2 (COX-2) plays a variety of roles in the gastrointestinal tract, including pathogenic processes such as neoplasia. Recently, we have generated transgenic mice that overexpress rat ErbB-2 under the control of bovine keratin 5 promoter (BK5.ErbB-2 mice). Homozygous BK5.ErbB-2 mice develop adenocarcinoma of gallbladder with an approximately 90% incidence. In addition to the activation of ErbB-2 and epidermal growth factor receptor, mRNA and protein levels of COX-2 were up-regulated in the gallbladder carcinomas that developed in these transgenic mice. The aim of this study was to examine the effects of a COX-2 inhibitor, CS-706, on the development of gallbladder carcinomas using the BK5.ErbB-2 mouse model. Ultrasound image analysis as well as histologic evaluation revealed a significant therapeutic effect of CS-706 on the gallbladder tumors, either as reversion to a milder phenotype or inhibition of tumor progression. The antitumor effect was associated with inhibition of prostaglandin E(2) synthesis. CS-706 treatment also down-regulated the activation of ErbB-2 and epidermal growth factor receptor, resulting in decreased levels of phosphorylated Akt and COX-2 in gallbladder cancers of BK5.ErbB-2 mice. Based on our results, targeting COX-2 could provide a potentially new and effective therapy alone or in combination with other therapeutic agents for patients with biliary tract cancer.
机译：由于胆道癌对常规疗法的敏感性较差以及无法预防或检测早期肿瘤形成，因此胆道癌的治疗和管理仍具有挑战性。胆囊癌最知名的危险因素是慢性炎症的存在，通常与胆结石有关。已经提出，环氧合酶-2（COX-2）在胃肠道中起多种作用，包括诸如瘤形成的致病过程。最近，我们已经产生了在牛角蛋白5启动子控制下过表达大鼠ErbB-2的转基因小鼠（BK5.ErbB-2小鼠）。纯合子BK5.ErbB-2小鼠发展为胆囊腺癌，发生率约为90％。除了激活ErbB-2和表皮生长因子受体外，在这些转基因小鼠中发育的胆囊癌中，COX-2的mRNA和蛋白水平也被上调。这项研究的目的是使用BK5.ErbB-2小鼠模型检查COX-2抑制剂CS-706对胆囊癌发展的影响。超声图像分析和组织学评估显示CS-706对胆囊肿瘤具有显着的治疗作用，既可以转变为较温和的表型，也可以抑制肿瘤的进展。该抗肿瘤作用与抑制前列腺素E（2）合成有关。 CS-706治疗还下调了ErbB-2和表皮生长因子受体的激活，导致BK5.ErbB-2小鼠胆囊癌中磷酸化的Akt和COX-2含量降低。根据我们的研究结果，靶向COX-2可以单独或与其他治疗剂联合为胆道癌患者提供潜在的新型有效疗法。

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