Enhancement of N-nitrosodiethylamine-initiated hepatocarcinogenesis caused by a colchicine-induced cell cycle disturbance in partially hepatectomized rats.
The effects of a colchicine-induced M-phase block of regeneration after partial hepatectomy on early-stage liver carcinogenesis were studied in rats. When administered 1 or 3 days after N-diethylnitrosamine initiation and partial hepatectomy, colchicine increased the mitotic index of regenerating hepatocytes at days 4-6 without evidence of liver cell necrosis. When the protocol was combined with a selection procedure (E. Cayama et al., Nature (Lond.), 275: 60-62, 1978), a significant increase in the size but not number of gamma-glutamyltranspeptidase-positive foci at week 5 was observed in a colchicine dose-dependent manner. This was associated with an elevated incorporation of 5-bromo-2-deoxyuridine into the gamma-glutamyltranspeptidase-positive cells. In a longer-term experiment, the numbers, sizes, and 5-bromo-2-deoxyuridine labeling index of persistent nodules were increased significantly in colchicine-treated rats at week 9. This was associated with significant increases in the incidences and numbers of hepatocellular carcinomas at week 42. The above results raise the interesting possibility that a cell cycle disturbance in the early stage of liver carcinogenesis provides a persisting growth advantage for initiated cells, resulting in enhanced growth of foci and persistent nodules that evolve into hepatocellular carcinomas.
Ohashi
K
K
Department of Oncological Pathology, Nara Medical University, Japan.
Tsutsumi
M
M
Tsujiuchi
T
T
Kobitsu
K
K
Okajima
E
E
Nakajima
Y
Y
Nakano
H
H
Takahashi
M
M
Mori
Y
Y
Konishi
Y
Y
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D003043:Cocarcinogenesis; D003078:Colchicine / Q000633:toxicity*; D004052:Diethylnitrosamine / Q000633:toxicity*; D006498:Hepatectomy; D066298:In Vitro Techniques; D008099:Liver / Q000033:anatomy & histology / Q000187:drug effects / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000209:etiology* / Q000473:pathology*; D008297:Male; D008938:Mitosis / Q000187:drug effects; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D009336:Necrosis; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D005723:gamma-Glutamyltransferase / Q000378:metabolism
D002273:Carcinogens; D009153:Mutagens; D004052:Diethylnitrosamine; D005723:gamma-Glutamyltransferase; D003078:Colchicine