Treatment of thioacetamide-induced liver cirrhosis by the Ras antagonist, farnesylthiosalicylic acid.
OBJECTIVE
Several studies have indicated increased expression of the Ras protooncogenes in liver cirrhosis. In a previous study in rats, we have shown that a synthetic Ras antagonist, S-farnesylthiosalicylic acid (FTS), could inhibit the development of liver cirrhosis. The aim of the current study was to examine whether FTS will accelerate the resolution of liver cirrhosis induced in rats by thioacetamide.


METHODS
Cirrhosis was induced in male Wistar rats by intraperitoneal (i.p.) administration of thioacetamide (200 mg/kg twice weekly for 12 weeks). In the treated group, the Ras antagonist FTS (5 mg/kg, i.p./3 times/week) was administered for 8 weeks after liver cirrhosis has already been established. Control cirrhotic rats received PBS injections for 8 weeks.


RESULTS
Rats treated with FTS for 8 weeks had lower histopathologic score of fibrosis (P = 0.01), lower hepatic hydroxyproline levels (P = 0.0002) and lower spleen weight (P = 0.02) than the cirrhotic rats treated with PBS. Following FTS treatment, the MMP-2 and MMP-9-induced collagenolytic activity and TIMP-2 expression, were increased in FTS-compared to PBS-treated rats. TUNEL assay of liver sections performed 8 weeks after thioacetamide withdrawal showed increased apoptotic figures in both groups (P = NS).


CONCLUSIONS
These results indicate that the Ras antagonist FTS accelerates the regression of experimentally-induced hepatic cirrhosis. The mechanism may involve increased collagenolytic activity.
Department of Pediatric Gastroenterology, Tel-Aviv, Souraski Medical Center, Tel-Aviv, Israel.
Shimon
S
Reif
Hussein
H
Aeed
Yael
Y
Shilo
Reuven
R
Reich
Yoel
Y
Kloog
Young Oh
YO
Kweon
Rafael
R
Bruck
D000818:Animals; D017209:Apoptosis; D005204:Farnesol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D011905:Genes, ras; D006909:Hydroxyproline / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D008297:Male; D045726:Metalloproteases / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012459:Salicylates / Q000494:pharmacology*; D013154:Spleen / Q000473:pathology; D013853:Thioacetamide; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism
D012459:Salicylates; C093323:farnesylthiosalicylic acid; D013853:Thioacetamide; D019716:Tissue Inhibitor of Metalloproteinase-2; D005204:Farnesol; D045726:Metalloproteases; D006909:Hydroxyproline