Different inhibitory effects in the early and late phase of treatment with KAT-681, a liver-selective thyromimetic, on rat hepatocarcinogenesis induced by 2-acetylaminofluorene and partial hepatectomy after diethylnitrosamine initiation.
We recently reported that short-term treatment with KAT-681 (KAT), a liver-selective thyromimetic, inhibits the development of preneoplastic lesions in rat livers and may be a candidate chemopreventive agent for hepatocarcinogenesis. In this study, time-course observations of hepatocellular proliferative lesions were carried out during short-term and long-term treatment with KAT to investigate its anti-hepatocarcinogenic effects. The hepatocellular proliferative lesions in male F344 rats were induced by the initiation treatment of diethylnitrosamine (DEN), followed by treatment with 2-acetylaminofluorene (2-AAF) and partial hepatectomy (PH). The rats were administered KAT orally at a dose of 0.25 mg/kg/day for 3 weeks (experiment 1) or 0.1 mg/kg/day for 20 weeks (experiment 2). In experiment 1, a serial reduction in the number of altered hepatocellular foci (AHF) with positive expression of glutathione S-transferase placental form (GST-P) was observed until day 14 of the treatment period. The proliferative index (PI) of hepatocytes in the AHF significantly increased in the KAT group throughout the treatment period, with a peak on day 2. KAT treatment showed no obvious effects on GST-P-positive hepatocellular adenomas (HCAs) at any time point. In contrast, long-term KAT treatment in experiment 2 revealed a reduction in the mean size of HCAs in addition to reductions in the number and mean size of AHF. The PIs within the lesions in KAT-treated rats were significantly lower than those in controls. The present study indicates that KAT has different inhibitory effects on hepatocarcinogenesis in the early and late phases of KAT treatment; there is a reduction in AHF with enhanced cell proliferation in the early phase and the inhibition of development of AHF and HCAs with suppression of cell proliferation in the late phase. These results may suggest further potential of KAT as a promising chemopreventive agent for hepatocarcinogenesis.
Hayashi
Morimichi
M
Toxicology Laboratories, Research and Development, Kissei Pharmaceutical Co. Ltd., Hotaka, Minamiazumi-gun, Nagano, Japan. morimichi_hayashi@pharm.kissei.co.jp
Tamura
Toru
T
Kuroda
Junji
J
Ohnota
Hideki
H
Shibata
Nobuo
N
Akahane
Masuo
M
Kashida
Yoko
Y
Mitsumori
Kunitoshi
K
D015073:2-Acetylaminofluorene / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D049109:Cell Proliferation / Q000187:drug effects; D004052:Diethylnitrosamine / Q000633:toxicity*; D004435:Eating / Q000187:drug effects; D005982:Glutathione Transferase / Q000378:metabolism; D006498:Hepatectomy; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects*; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D008297:Male; D008314:Malonates / Q000494:pharmacology*; D009929:Organ Size / Q000187:drug effects; D010647:Phenyl Ethers / Q000494:pharmacology*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D013963:Thyroid Hormones / Q000494:pharmacology*
D016588:Anticarcinogenic Agents; D002273:Carcinogens; D008314:Malonates; C496199:N-(4-(3-((4-fluorophenyl)hydroxymethyl)-4-hydroxyphenoxy)-3,5-dimethylphenyl) malonamic acid sodium; D010647:Phenyl Ethers; D018809:Proliferating Cell Nuclear Antigen; D013963:Thyroid Hormones; D004052:Diethylnitrosamine; D015073:2-Acetylaminofluorene; D005982:Glutathione Transferase