A number of the characteristics of the stages of initiation and promotion during multistage hepatocarcinogenesis in the rat have been defined in several laboratories. One characteristic of tumor promotion during multistage hepatocarcinogenesis in the rat, seen in virtually all models reported for the study of this process, is the instability of the early initial focal lesions that result from the initiation process followed by a short period of promotion. It is the aim of this proposal to study the quantitative aspects of the reversibility of lesions occurring during promotion in vivo in multistage hepatcocarcinogenesis in the rat and to investigate the cell and molecular biology of cell populations formed during tumor promotion in this system. The quantitative relationships of the number and volume of enzyme-altered foci following removal and subsequent readministration of a promoting agent as well as the effect of altering the administration schedule of the promoting agent will be investigated. These studies will be carried out in several different models including those reported by Solt and Farber, Peraino, and Pitot et al. Since preliminary investigations in the Pitot model have indicated that some but not all such focal lesions are lost on removal of the promoting agent, these investigations will also be directed at defining any differences between those enzyme-altered foci present during administration of a promoting agent and those remaining following removal of the promoting agent. To study the cell and molecular biology of these altered cell populations occurring during tumor promotion, hepatocytes isolated from enzyme- altered foci as well as those not present in such foci will be investigated with respect to the regulation of DNA synthesis in cell culture, as well as the regulation of genetic expression of both gamma-glutamyltranspeptidase and several proto-oncogenes in response to promoting agents and growth factors. Cells isolated from enzyme-altered foci and maintained in cell culture will be studied with respect to their capacity for the repair of DNA damage and the retention of DNA strand breaks compared with these parameters in hepatocytes not exhibiting characteristics of the enzyme-altered foci. These studies are based on the proposal that tumor promotion during multistage hepatocarcinogenesis is reversible and that the majority of the cells making up the enzyme-altered foci that develop during tumor promotion are dependent on the presence of a promoting agent.
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