Kiguchi Kaoru, Ruffino Lynnsie, Kawamoto Toru, Franco Eugenia, Kurakata Shin-ichi, Fujiwara Kosaku, Hanai Masaharu, Rumi Mohammad, DiGiovanni John
Department of Carcinogenesis, The University of Texas M. D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957, USA.
Mol Cancer Ther. 2007 Jun;6(6):1709-17. doi: 10.1158/1535-7163.MCT-07-0015.
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.
由于对传统疗法敏感性差，且无法预防或检测早期肿瘤形成，胆道癌的治疗和管理仍然具有挑战性。胆囊癌最广为人知的危险因素是存在慢性炎症，通常与胆结石有关。有人提出，环氧合酶-2（COX-2）在胃肠道中发挥多种作用，包括肿瘤形成等致病过程。最近，我们培育出了在牛角蛋白5启动子（BK5.ErbB-2小鼠）控制下过表达大鼠ErbB-2的转基因小鼠。纯合BK5.ErbB-2小鼠发生胆囊腺癌的发生率约为90%。除了ErbB-2和表皮生长因子受体的激活外，在这些转基因小鼠发生的胆囊癌中，COX-2的mRNA和蛋白水平上调。本研究的目的是使用BK5.ErbB-2小鼠模型研究COX-2抑制剂CS-706对胆囊癌发生发展的影响。超声图像分析以及组织学评估显示，CS-706对胆囊肿瘤具有显著的治疗效果，表现为恢复为较轻的表型或抑制肿瘤进展。抗肿瘤作用与前列腺素E2合成的抑制有关。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Akt和COX-2水平降低。根据我们的结果，靶向COX-2可能为胆道癌患者单独或与其他治疗药物联合提供一种潜在的新的有效治疗方法。
