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 alpha (RXRalpha) 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 RXRalpha. 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 RXRalpha 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.
Liu
Weidong
W
Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501.
Nakamura
Hideji
H
Tsujimura
Tohru
T
Cheng
Jidong
J
Yamamoto
Teruhisa
T
Iwamoto
Yuna
Y
Imanishi
Hiroyasu
H
Shimomura
Soji
S
Yamamoto
Tetsuo
T
Hirasawa
Tsutomu
T
Inagaki
Shuichiro
S
Nishiguchi
Shuhei
S
Hada
Toshikazu
T
D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D018890:Chemoprevention; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D015232:Dinoprostone / Q000097:blood; D017308:Etodolac / Q000627:therapeutic use*; D005234:Fatty Liver / Q000150:complications*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis / Q000378:metabolism; D047490:Retinoid X Receptor alpha / Q000032:analysis / Q000378:metabolism
D016588:Anticarcinogenic Agents; D052246:Cyclooxygenase 2 Inhibitors; D018809:Proliferating Cell Nuclear Antigen; D047490:Retinoid X Receptor alpha; D017308:Etodolac; D015232:Dinoprostone