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Cell Cycle-dependent Initiation of Hepatocarcinogenesis in Rats by Methyl(acetoxymethyl)nitrosamine¹

Department of Pathology and Lineberger Cancer Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27514 [W. K. K., D. G. K.]; Laboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick Cancer Research Facility, Frederick, Maryland 21701 [J. M. R.]; and Microbiological Associates, Inc., Bethesda, Maryland 20816 [M. L. W., D. D.]

Hepatocyte sensitivity to initiation of carcinogenesis was studied as a function of the cell cycle phase in which damage was incurred. Hepatocytes were stimulated to proliferate by a two-thirds partial hepatic resection, and their proliferation was synchronized further by postsurgical treatment with hydrocortisone. Groups of male F344 rats were given a single administration of methyl(acetoxymethyl)nitrosamine, a highly reactive methylating agent, at various times after two-thirds partial hepatic resection when hepatocytes were in defined phases of the cell cycle. Beginning 3 wk after the treatment and for 37 wk thereafter, rats were fed a diet containing 0.05% phenobarbital to promote the expression of initiated hepatocytes. At 45 wk after treatment with carcinogen hepatocytic neoplasms were enumerated. The greatest yield of neoplasms (5.4 per liver) was observed in the group treated 16 h after two-thirds partial hepatic resection or at the time when proliferating hepatocytes began to enter the S phase of the cell cycle. The least yield of neoplasms (0.8 per liver) was identified in the group treated with methyl(acetoxymethyl)nitrosamine when hepatocytes were early in G₁. In the proliferating hepatocytes sensitivity rose continuously during G₁ to a peak at the G₁-S border and then fell continuously as hepatocytes traversed S, G₂, and M. This pattern of response could not be attributed to variation in hepatic esterase which activates methyl(acetoxymethyl)nitrosamine or to variation in methylation of DNA. The results support a model in which carcinogen-induced genetic alterations, occurring at the time of or soon after damaged cells enter the S phase, represent irreversible events that contribute to the initiation of carcinogenesis.

¹ Supported in part by NIH Grant CA33238.

² To whom requests for reprints should be addressed, at 351 Lineberger Cancer Research Center 237H, University of North Carolina, Chapel Hill, NC 27514.

Received 7/14/86. Revised 10/ 9/86. Accepted 11/19/86.