Chemoprevention of spontaneous development of hepatocellular carcinomas in fatty liver Shionogi mice by a cyclooxygenase‐2 inhibitor

Cyclooxygenase 2 (COX-2) and retinoid X receptor α (RXRα) are suggested to have roles in carcinogenesis. COX-2 inhibitors have been reported to suppress growth of hepatocellular carcinoma (HCC) cell lines in vitro. However, little is known about the preventive effect of these drugs on spontaneous hepatocarcinogenesis in vivo. Etodolac exists in a racemic mixture containing S- and R-etodolac. S-etodolac is responsible for COX-2 inhibitory activity and R-etodolac is related to the downregulation of RXRα. Here, the effect of etodolac on spontaneous development of HCC in fatty liver Shionogi mice is evaluated. Etodolac was administered at a low (2 mg/kg) or high (10 mg/kg) dose three times a week for 16 months starting at the age of 3 months. The development of HCC was suppressed slightly in the high-dose group, and suppressed markedly in the low-dose group, although the development of fatty liver was not inhibited in either group. Plasma prostaglandin E2 levels were also decreased significantly in the low-dose group, consistent with the suppression of HCC. The expression of RXRα and proliferating cell nuclear antigen in non-tumorous liver tissues was decreased significantly in both the low-dose and high-dose groups. These findings show that etodolac treatment at an optimum dose suppresses hepatocarcinogenesis in vivo, and may be useful for preventing the development of HCC in humans. (Cancer Sci 2006; 97: 768–773)