Effect of anticancer agents on cell cycle of regenerating hepatocytes in rats.
The effect of three anticancer agents, cisplatin, doxorubicin, and mitomycin, on liver regeneration after 70% partial hepatectomy in rats was investigated by total DNA content of the liver and flow cytometric analysis of hepatocyte nuclei using two-color staining of anti-bromodeoxyuridine monoclonal antibody and propidium iodide. Total DNA content of regenerating liver 7 days after hepatectomy showed significant suppression of regeneration by these agents (P less than 0.01). The inhibitory effects of the agents on the cell cycle of hepatocytes by flow cytometric analysis were (1) a delay of the peak or a decrease in the proportion of S phase nuclei and/or (2) polyploidization of the nuclei, demonstrated by accumulation of 8c and occasionally 16c nuclei, of which the DNA contents were four and eight times as much as that of diploid (2c) cell nuclei, respectively. The former (1) suggests G0 or G1 phase block, and the latter (2) G2 phase block. In terms of total DNA content of regenerating liver, the inhibitory effect was most prominent in the cisplatin-administered groups. The polyploidization of nuclei was most remarkable in the mitomycin-administered groups. Although the total DNA content recovered to the level of control at 6 weeks after hepatectomy, the polyploidization effect persisted in the drug-administered groups. These agents had no cytocidal action on proliferating hepatocytes as can be seen from the aspartate aminotransferase and alanine aminotransferase serum levels. We conclude that in a short-term observation, the anti-cancer agents significantly inhibit liver regeneration, although the inhibitory effect on DNA synthesis does not last long.(ABSTRACT TRUNCATED AT 250 WORDS)
Tamura
J
J
1st Department of Surgery, Faculty of Medicine, Kyoto University, Japan.
Tanaka
J
J
Fujita
K
K
Yoshida
M
M
Kasamatsu
T
T
Arii
S
S
Tobe
T
T
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D002945:Cisplatin / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D005434:Flow Cytometry; D006498:Hepatectomy; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000648:ultrastructure; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D008937:Mitomycins / Q000494:pharmacology; D011003:Ploidies; D051381:Rats; D011919:Rats, Inbred Strains
D000970:Antineoplastic Agents; D008937:Mitomycins; D004317:Doxorubicin; D004247:DNA; D002945:Cisplatin