Prevention of rat hepatocarcinogenesis by acyclic retinoid is accompanied by reduction in emergence of both TGF-alpha-expressing oval-like cells and activated hepatic stellate cells.
We investigated the preventive effects of a synthetic acyclic retinoid, NIK-333, on the early and late events of hepatocarcinogenesis in male F344 rats treated with 3'-methyl-4-dimethylaminoazobenzene (3'-MeDAB). NIK-333 was administered once a day on consecutive days at a dose of 10, 40, or 80 mg/kg body weight along with the supplementation with 3'-MeDAB-containing diet for 16 wk. Animals from each group were sacrificed at 4 and 16 wk after the commencement of the experiment to determine the effect of NIK-333 on the early and late stages of carcinogenesis, respectively. NIK-333 suppressed the emergence of both oval-like cells expressing transforming growth factor (TGF)-alpha, putative progenitors of hepatocellular carcinoma (HCC), and activated hepatic stellate cells, major matrix-producing cells of the liver, in the early stage and inhibited the incidence of HCC in the late phase. These results suggest that NIK-333 is a promising drug for the chemoprevention of HCC by uniquely suppressing the early events of hepatocarcinogenesis, that is, development of both oval-like cells and fibrogenesis.
Sano
Tetsuro
T
Pharmaceutical Research Laboratories, Nikken Chemicals Co., Saitama, Japan.
Kagawa
Masataka
M
Okuno
Masataka
M
Ishibashi
Naoto
N
Hashimoto
Manabu
M
Yamamoto
Megumi
M
Suzuki
Rikako
R
Kohno
Hiroyuki
H
Matsushima-Nishiwaki
Rie
R
Takano
Yukihiko
Y
Tsurumi
Hisashi
H
Kojima
Soichi
S
Friedman
Scott L
SL
Moriwaki
Hisataka
H
Tanaka
Takuji
T
D000199:Actins / Q000187:drug effects / Q000378:metabolism*; D000236:Adenoma / Q000139:chemically induced / Q000517:prevention & control*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use*; D002277:Carcinoma / Q000139:chemically induced / Q000517:prevention & control*; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005355:Fibrosis / Q000517:prevention & control; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D008749:Methyldimethylaminoazobenzene / Q000008:administration & dosage / Q000031:analogs & derivatives; D051381:Rats; D011916:Rats, Inbred F344; D012176:Retinoids / Q000627:therapeutic use; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013997:Time Factors; D016211:Transforming Growth Factor alpha / Q000187:drug effects / Q000378:metabolism*; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use
D000199:Actins; D000970:Antineoplastic Agents; D008749:Methyldimethylaminoazobenzene; D012176:Retinoids; D016211:Transforming Growth Factor alpha; D014212:Tretinoin; C498862:Acta2 protein, rat; C487689:(2E,4E,6E,10E)-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid; C035722:3'-methyl-4-diethylaminoazobenzene; C034534:3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid