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.
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