Effect of hepatocyte growth factor on endogenous hepatocarcinogenesis in rats fed a choline-deficient L-amino acid-defined diet.
Hepatocyte growth factor (HGF) is a promising agent for the treatment of intractable liver disease, due to its mitogenic, anti-apoptotic, and anti-fibrotic effects. We investigated the effect of recombinant human HGF (rh-HGF) on the development of both hepatocellular carcinoma (HCC) and preneoplastic nodules in rats fed a choline-deficient L-amino acid-defined (CDAA) diet, an animal model of hepatocarcinogenesis resembling human development of HCC with cirrhosis. From weeks 13 to 48 of the CDAA diet, rh-HGF (0.1 or 0.5 mg/kg/day) was administered intravenously to rats in four-week cycles, with treatment for five consecutive days of each week for two weeks, followed by a two-week washout period. Treatment with rh-HGF significantly inhibited the development of preneoplastic nodules in a dose-dependent manner at 24 weeks. Although the numbers and areas of the preneoplastic nodules in rats treated with rh-HGF were equivalent to those in mock-treated rats by 60 weeks, the incidence of HCC was reduced by HGF treatment. Although one rat treated with low-dose rh-HGF exhibited a massive HCC, which occupied almost the whole liver, and lung metastases, HGF treatment did not increase the overall frequency of HCC. Administration of high-dose rh-HGF, however, induced an increase in the urinary excretion of albumin, leading to decreased serum albumin at 60 weeks. These results indicate that long-term administration of rh-HGF does not accelerate hepatocarcinogenesis in rats fed a CDAA diet. However, these findings do not completely exclude the potential of HGF-induced hepatocarcinogenesis; this issue must be resolved before rh-HGF can be used for patients with intractable liver diseases, especially those with cirrhosis.
Nakanishi
Chihiro
C
Department of Internal Medicine II, Faculty of Medicine, University of Miyazaki Kiyotake, Miyazaki 880-1601, Japan.
Moriuchi
Akihiro
A
Ido
Akio
A
Numata
Masatsugu
M
Kim
Il-Deok
ID
Kusumoto
Kazunori
K
Hasuike
Satoru
S
Abe
Hiroo
H
Nagata
Kenji
K
Akiyama
Yutaka
Y
Uto
Hirofumi
H
Kataoka
Hiroaki
H
Tsubouchi
Hirohito
H
D000418:Albumins / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism*; D000821:Animal Feed; D000818:Animals; D002794:Choline / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology / Q000378:metabolism*; D008175:Lung Neoplasms / Q000556:secondary; D008297:Male; D009362:Neoplasm Metastasis; D051381:Rats; D011916:Rats, Inbred F344; D011994:Recombinant Proteins / Q000378:metabolism
D000418:Albumins; D000596:Amino Acids; D011994:Recombinant Proteins; D017228:Hepatocyte Growth Factor; D002794:Choline