Mitomycin C-induced acceleration of liver cell polyploidization in adult rat after partial hepatectomy.
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Mitomycin C, a DNA cross-linking agent, was administered for a week intraperitoneally to a normal 9-week-old rat in which hepatocyte proliferative activity had almost ceased. In the rat treated with mitomycin C, the number of polyploid cells with the DNA amounts more than 4C was not increased in comparison with that in the control rat without any treatment. However, the partial hepatectomy in the rat pretreated with mitomycin C provoked prominent hepatocyte polyploidization much greater in degree than that found in the hepatectomized rat without mitomycin C treatment. These results seem to indicate that the existence of cross-linking DNA damages is a latent factor necessary for the induction of abortive mitosis of a cell after completion of DNA synthesis, which results in the production of a mononuclear polyploid cell in one-step higher DNA class. Cross-linking DNA damages and DNA synthesis are the essential factors for the manifestation of polyploidization.Keywords:
Mitomycin C
Polyploid
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A cross-linking agent (actinomycin D or mitomycin C) was administered to newborn rats with liver cells actively proliferating in diploid state, to test our recently proposed hypothesis that polyploidization and binucleate formation become manifest, under abortive cell proliferation, in nucleus with cross-links between double strands of DNA. The polyploidization of hepatocyte nuclei was analysed by Feulgen cytofluoromertric method with smear preparations, and binucleate formation was determined on section preparations. The number of polyploid and binuclear cells increased in rat liver treated with a cross-linking agent in comparison with the control. This finding supports our cross-linkage hypothesis.
Polyploid
Mitomycin C
Feulgen stain
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Mitomycin C, a DNA cross-linking agent, was administered for a week intraperitoneally to a normal 9-week-old rat in which hepatocyte proliferative activity had almost ceased. In the rat treated with mitomycin C, the number of polyploid cells with the DNA amounts more than 4C was not increased in comparison with that in the control rat without any treatment. However, the partial hepatectomy in the rat pretreated with mitomycin C provoked prominent hepatocyte polyploidization much greater in degree than that found in the hepatectomized rat without mitomycin C treatment. These results seem to indicate that the existence of cross-linking DNA damages is a latent factor necessary for the induction of abortive mitosis of a cell after completion of DNA synthesis, which results in the production of a mononuclear polyploid cell in one-step higher DNA class. Cross-linking DNA damages and DNA synthesis are the essential factors for the manifestation of polyploidization.
Mitomycin C
Polyploid
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Liver cell
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Polyploid
Liver Regeneration
Thymidine
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By applying autoradiography with 3H-thymidine hepatocytes of young adult guinea pigs were found to enter the DNA-synthesis phase 25 hours after partial hepatectomy. Peaks of nuclei labeling were revealed 30, 45, and 60 hours after the operation. By calculating mitotic figures on squash preparations two waves of mitosis were found (in 40 and 55 hours) after hepatectomy. Cytophotometric study of DNA content showed practically all mononuclear and binuclear hepatocytes to contain diploid nuclei in 3 and 5 days after the operation. By the end of the 7th regeneration day there were revealed 6% mononuclear tetraploid cells. The percentage of binuclear cells during the period of regeneration under study decreased from 16 to 8%. A conclusion was drawn that the main cytologicalmechanism of the guinea pig liver regeneration was full-fledged mitosis ending by cell division.
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Thymidine
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Abstract The effect of chlorambucil on the colony‐forming ability of HeLa cells following either treatment for 1 h or continuous treatment has been measured. Concentrations of chlorambucil which had only minimal effects on cell survival inhibited the rate of DNA but not RNA and protein synthesis within 1 h of treatment. Nevertheless, cells continued to synthesize DNA for many hours after this treatment in the absence of cell division. Synchronous populations of HeLa cells treated prior to DNA synthesis, in the G 1 phase of the cell cycle, were not delayed in their progression into the S phase where they exhibited a marked dose‐dependent inhibition of the rate of DNA synthesis. Cells in which DNA synthesis had been depressed showed a prolongation of the S phase and this was accompanied by a corresponding dose‐dependent mitotic delay. Treatment during the G 2 phase of the cell cycle did not induce any delay or block in the next mitosis, but did inhibit the rate of DNA synthesis in the following cell cycle in a dosedependent manner; this depression of DNA synthesis was followed by a delay in the next mitosis. Cross‐linking of either isolated DNA or DNA present in treated HeLa cells was demonstrated, and in the latter case calculated to be of the same order as that which occurred with other difunctional agents at comparable toxic concentrations.
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The processes of polyploidization in normal human liver parenchyma from 155 individuals aged between 1 day and 92 years were investigated by Feulgen-DNA cytophotometry. It was shown that polyploid hepatocytes appear in individuals from 1 to 5 years old. Up to the age of 50 years the accumulation rate of binucleate and polyploid cells is very slow, but subsequently hepatocyte polyploidization is intensified, and in patients aged 86-92 years the relative number of cells with polyploid nuclei is about 27%. Only a few hepatocytes in the normal human liver reach 16C and 8C x 2 ploidy levels for mononucleate and binucleate cells respectively. Using a mathematical modeling method, it was shown that during postnatal liver growth the polyploidization process in human liver is similar to that in the rat, and that polyploid cells are formed mainly from binucleate cells. As in rats, prior to an increase in ploidy level, diploid human hepatocytes can pass several times through the usual mitotic cycles maintaining their initial ploidy level. After birth, only one in ten hepatocytes starting DNA synthesis enters the polyploidization process. At maturity about 60% of 2C-hepatocytes starting DNA synthesis divide by conventional mitosis, the rest dividing by acytokinetic mitosis leading to the formation of binucleate cells. During ageing the probability of hepatocyte polyploidization increases and in this period there are two polyploid or binucleate cells for every diploid dividing by conventional mitosis.
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