In order to complete our studies of factors influencing the initiation of hepatocarcinogenesis, the survival of damaged hepatocytes must be enumerated. The yield of hepatocytic neoplasms is the product of the frequency of induced events per survivor and the surviving fraction. Cell cycle-dependent variation in survival must be factored into the results of the previous studies in which yields of neoplasms were enumerated. Several methods will be applied to assess cell survival after carcinogen treatment including in situ staining with trypan blue dye and colonization of fat pads by isolated hepatocytes. With an estimate of cytotoxicity the frequencies with which hepatocarcinogens initiate carcinogenesis can be determined. With an improved measure of initiation frequency we can quantify the effects of different carcinogens at equitoxic doses. We have found that three carcinogens that produce quite different spectra of lesions in DNA display differences in their abilities to induce islands of cellular alteration and neoplasms. At doses of the carcinogens producing nearly equal numbers of islands, the methylating agent, DMN-Ac, produced multiple neoplasms in every liver, the arylalkylating agent, BPDE, produced a few neoplasms with moderate incidence, and the physical carcinogen, gamma radiation, produced no tumors. We will establish for each of the three carcinogens quantitative dose-response curves for frequencies of carcinogenic initiations and cellular alterations in sensitive and resistant populations. Because of the possibility of variable latencies for neoplasms initiated by the three carcinogens we also will perform time-course studies to determine initiation and alteration frequencies after a single dose given to sensitive populations. Finally we will establish the frequencies and timing of appearance of cell populations which express an altered oncogene product or aneuploidy. Thus we will determine which alterations are seen in livers that have low probability to develop neoplasms and which are seen in livers with high probability. In this way we will begin to define the specific alterations that provoke the neoplastic phenotype in hepatocytes that have been damaged when in sensitive or resistant cell cycle phases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA032238-04
Application #
3170202
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1982-08-01
Project End
1987-07-31
Budget Start
1985-08-01
Budget End
1986-07-31
Support Year
4
Fiscal Year
1985
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Kaufmann, W K; Rice, J M; MacKenzie, S A et al. (1991) Proliferation of carcinogen-damaged hepatocytes during cell-cycle-dependent initiation of hepatocarcinogenesis in the rat. Carcinogenesis 12:1587-93
Brylawski, B P; Cordeiro-Stone, M; Kaufman, D G (1989) Ferritin-labeled rabbit Fab fragments for the single-step detection of benzo[a]pyrene-diol-epoxide adducts in DNA by electron microscopy. Carcinogenesis 10:199-202
Kaufmann, W K; Ririe, D G; Kaufman, D G (1988) Phenobarbital-dependent proliferation of putative initiated rat hepatocytes. Carcinogenesis 9:779-82
Goyette, M; Dolan, M; Kaufmann, W et al. (1988) Transforming activity of DNA from rat liver tumors induced by the carcinogen methyl(acetoxymethyl)nitrosamine. Mol Carcinog 1:26-32
Kaufmann, W K; MacKenzie, S A; Kaufman, D G (1987) Factors influencing the initiation by gamma rays of hepatocarcinogenesis in the rat. Teratog Carcinog Mutagen 7:551-6
Kaufmann, W K; Tsao, M S; Novicki, D L (1986) In vitro colonization ability appears soon after initiation of hepatocarcinogenesis in the rat. Carcinogenesis 7:669-71
Kaufmann, W K; MacKenzie, S A; Rahija, R J et al. (1986) Quantitative relationship between initiation of hepatocarcinogenesis and induction of altered cell islands. J Cell Biochem 30:1-9
Kaufmann, W K; MacKenzie, S A; Kaufman, D G (1985) Quantitative relationship between hepatocytic neoplasms and islands of cellular alteration during hepatocarcinogenesis in the male F344 rat. Am J Pathol 119:171-4