Suppression of Hepatoma Cell Growth by Celecoxib

描述(由申请人提供)： 肝细胞癌是世界上最常见的恶性肿瘤之一，约占人类所有癌症的6%，每年导致100万人死亡。肝癌的发病率上升，治疗有限，预后差，迫切需要探索有效的化学预防策略。环氧合酶-2(COX-2)的过度表达与肝癌的发生有关。塞来昔布是一种选择性COX-2抑制剂，可抑制结肠癌和其他恶性肿瘤的生长，最近已被FDA批准用于结肠癌的化学预防。尽管我们之前的体外研究表明塞来昔布对人肝癌细胞的生长有很强的抑制作用，但这种作用从未在体内进行过测试。针对PAR 02-176，我们建议研究塞来昔布对人肝癌裸鼠移植瘤生长的影响及其机制。两种不同的人肝癌细胞系，COX-2表达Huh7和COX-2不表达PLC/PRF/5，将被接种到裸鼠皮下建立肝癌移植瘤。塞来昔布或对照组小鼠以灌胃的方式给药。该模型将被用来研究我们的两个特定目的：(1)确定塞来昔布对表达COX-2的Huh7和COX-2不表达的PLC/PRF/5肝癌移植瘤生长的影响。(2)探讨塞来昔布抑制肝癌移植瘤生长的体内机制。移植肝癌的大小和血浆甲胎蛋白水平将作为主要终点来评估塞来昔布对肝癌移植瘤生长的影响。将测试环氧合酶-2的催化活性、细胞周期进程的改变和细胞凋亡，以确定塞来昔布介导的机制。这些实验结果将为了解塞来昔布在体内抑制异种肝癌生长的程度和机制提供重要信息，这是未来临床试验测试塞来昔布作为肝癌化学预防的临床药物必不可少的一步。

DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, accounting for approximately six percent of all human cancers and one million deaths annually. The rising incidence, limited treatment, and poor prognosis of HCC emphasize an urgent need to explore innovative strategies for effective chemoprevention of this disease. Overexpression of cyclooxygenase-2 (COX-2) has been associated with hepatocarcinogenesis. Celecoxib, a selective COX-2 inhibitor, suppresses growth of colon cancer and other malignancies and has recently been approved by FDA for chemoprevention of colon cancer. Even though our previous in vitro studies have indicated a potent inhibitory effect of celecoxib on growth of human HCC cells, such effect has never been tested in vivo. In response to PAR 02-176, we propose to determine the in vivo effect and mechanisms of celecoxib on growth of human HCC xenografts in nude mice. Two different human HCC cell lines, COX-2 expressing HuH7 and COX-2 non-expressing PLC/PRF/5, will be subcutaneously inoculated into nude mice to create HCC xenografts. Either celecoxib or control vehicle will be administered to these mice by gavage feeding. This model will be used to investigate our two specific aims: (1) To determine the in vivo effects of celecoxib on growth of COX-2 expressing HuH7 and COX-2 non-expressing PLC/PRF/5 HCC xenografts. (2) To examine the in vivo mechanisms of celecoxib-induced growth inhibition of these HCC xenografts. The size of HCC xenografts and level of plasma alpha fetoprotein will be used as primary end points to assess the effect of celecoxib on growth of HCC xenografis. COX-2 catalytic activity, alteration of cell cycle progression and apoptosis will be tested for celecoxib-mediated mechanisms. The results of these experiments will provide important information on degree and mechanisms of celecoxibmediated growth inhibition of HCC xenografis in vivo, which is an essential step for future clinical trials to test celecoxib as a clinical agent for HCC chemoprevention.