Intrahepatic cholangiocarcinoma (CCA) incidence and mortality rates are rising in the United States and worldwide. Prognosis has not improved in twenty years with advances in surgical techniques and chemotherapeutics. Main risk factors for CCA (liver flukes in Asia, primary sclerosing cholangitis in the US) have pathophysiologies of chronic inflammation. Cyclooxygenase-2 (COX-2) is induced during the inflammatory response and is not expressed in normal bile ducts. Also, studies have shown that COX-2 expression is up-regulated in human CCA. Therefore, COX-2 represents a potential target of chemotherapy and/or chemoprevention. AIMS: This study examines chemopreventative effects of the non-specific COX-2 inhibitor sulindac in a chemical carcinogenesis model of CCA in female Syrian Golden hamsters. To avoid cardiovascular risks linked with long-term COX-2-specific inhibition, a non-specific inhibitor was used. METHODS: A rapid induction model for CCA development was employed. Fifty female Syrian golden hamsters underwent subcutaneous injection with the carcinogenic nitrosamine N-nitrosobis(2-oxopropyl)amine (BOP), followed by ethionine/methionine augmentation pressure protocol. There were 4 treatment groups: group 1 (control), group 2 (sulindac 50 mg/kg body weight, BW), group 3 (sulindac 100 mg/kg BW), and group 4 (sulindac 150 mg/kg BW) which were concurrently gavaged. At 12 weeks post-initiation, remaining animals were sacrificed. RESULTS: Histopathological examination of H&E stained liver sections revealed significant chemopreventative effects of sulindac treatment on the number of macroscopic ( > 2 mm maximal diameter) CCAs formed. There were 2.2 lesions/animal in group 1 (control), 1.33 lesions/animal in group 2 (50 mg/kg), 0.5 lesions/animal in group 3 (100 mg/kg) and 0.33 lesions/animal in group 4 (150 mg/kg). Overall, there was a statistically significant decrease (P<0.05) in average CCA size in groups 2 (52 x 103 ± 4.2 x 103 μm2), 3 (62 x 103 ± 13 x 103 μm2), and 4 (54 x 103 ± 21 x 103 μm2) as compared with control (294 x 103 ± 88 x 103 μm2). Similarly, the average size of pre-cancerous bile duct malformations decreased in groups 2 (14 x 103 ± 1.6 x 103 μm2), 3 (16 x 103 ± 1.6 x 103 μm2), and 4 (8.0 x 103± 0.7 x 103 μm2) as compared with control (96 x 103 ± 1 x 103 μm2, P<0.05). CONCLUSIONS: We demonstrate a decrease in average sizes of cancerous and precancerous biliary tract lesions using low-dose sulindac, which may also avoid risks of complications of inhibiting COX-2. We also show a dose-dependent decrease in macroscopic cholangiocarcinoma formation in hamsters undergoing sulindac chemoprevention. These data suggest COX plays an early critical role cholangiocarcinoma carcinogenesis.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]