The present proposal reflects our ongoing efforts to understand the initiation phase of the carcinogenic process at molecular level. The rationale for the investigation stems from our recent observation that mitogen-induced liver cell proliferative stimulus, unlike compensatory liver cell proliferative stimulus did not achieve initiation phase of the liver carcinogenic process. This observation was very significant because even though both types of stimuli induce liver cell proliferation one (compensatory type) achieves initiation while the other (mitogen-induced) does not. In our opinion an in depth analysis of this intriguing phenomenon may reveal the molecular mechanisms by which compensatory cell proliferation achieves initiation process. In initial experiments rats will be given non-necrogenic doses of carcinogens at the peak of liver DNA synthesis induced by liver mitogens and PH or CC14. The initiated hepatocytes will be promoted to grow and form foci of enzyme altered hepatocytes, hepatic nodules and hepatocellular carcinoma. To establish the generality of the phenomenon, three different initiators; four different liver mitogens such as lead nitrate, cyproterone acetate, nafenopin and ethylene dibromide and two different promoters such as orotic acid and phenobarbital will be used. In the next series, experiments will be designed to test the hypothesis that mitogen-induced liver cell proliferation, like compensatory liver cell proliferation achieves initiation but the initiated hepatocytes are selectively lost by apoptosis during the regression phase that accompanies mitogen-induced liver cell proliferation. Since this study approaches differently into the role of cell proliferation in initiation phase we may be in for several pleasant surprises. In addition, if initiated hepatocytes are uniquely susceptible to apoptosis, can this be an efficient means of eliminating the initiated hepatocytes.
