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Cell Cycle Kinetics of Rat Hepatocytes in Early Putative Preneoplastic Lesions in Hepatocarcinogenesis¹

Department of Pathology, University of Toronto, Toronto, Ontario, Canada M5S 1A8 [J. R., E. F.]; Department of Mathematical Sciences, McMaster University, Hamilton, Ontario, CanadaL8S 4J9 [P. D. M. M.]; and Institute of Pathology, University of Munich, Munich, Federal Republic of Germany [H. M. R.]

This set of experiments is the first of a series designed to explore facets of cell proliferation of hepatocytes during the carcinogenic process induced in liver by chemical carcinogens. A rat model for hepatocarcinogenesis, the resistant hepatocyte model, was used. A major advantage of this model is the unusual degree of synchrony in the early steps. Carcinogenesis was initiated by the administration of a necrogenic dose of diethylnitrosamine. Resistant hepatocytes so induced were stimulated rapidly to proliferate by partial hepatectomy in the presence of a brief exposure to dietary 2-acetylaminofluorene sufficient to inhibit the proliferation of the majority of hepatocytes, the nonresistant population. Cell cycle parameters were measured in the early carcinogen-altered resistant hepatocyte populations and in regenerating hepatocytes. Growth fraction and doubling time were experimentally determined in the altered hepatocytes. The mean cell cycle length of the resistant cells was 38.6 hr, somewhat longer than that of regenerating hepatocytes, which was 33.6 hr. Most of the increase was due to a prolonged S phase which was 13.6 hr in the altered cell population as compared to 7.0 hr in hepatocytes in regenerating control liver. The hepatocytes in normal regenerating liver had a mean duration of 21.6 hr for G₁ as compared to 20.4 hr for the altered hepatocytes and a G₂ of 3.4 hr as compared to 3.0 hr for carcinogen-altered hepatocyte. M was assumed to be 1.6 hr in both populations. The growth fraction in the altered cell population was determined to be a minimum of 0.83, and the doubling time was about 45 hr. Thus, the resistant hepatocytes which represent an early putative preneoplastic population show, in general, a prolongation of the cell cycle, mostly due to a prolonged S phase.

¹ This research was supported by grants from the National Cancer Institute of Canada, the Medical Research Council of Canada (MT-5994), the National Cancer Institute, USPHS (CA-21157), Deutsche Forschungsgemeinschaft (RA 101/24-2) and Deutsche Stiftung für Krebsforschung.

² To whom requests for reprints should be addressed.

Received 8/ 1/83. Accepted 4/11/84.

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