233 Cancer Letters. (1991) 233 - 238 Elsevier Scientific Publishers Ireland Ltd. Stimulation of DNA synthesis by rat plasma following in vivo treatment with three liver mitogens P. Coni, G. Pichiri-Coni, G.M. Ledda-Columbano, E. Semple”, S. Rajalakshmi”, P.M. Raoa, D.S.R. Sarmaa and A. Columbano zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFE fstituto di Patologia Sperimentale. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA Uniue rsitd di Cagliari. Via zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONM Porcell 4 09124 Caglian (Italy ) and ‘Department zyxwvutsrqp of Pathology. University of Toronto. Toronto. Ontario (Canada) (Received 30 July 1991) (Revision received 8 October 1991) (Accepted 8 October 1991) zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA Summary Introduction zyxwvutsrqponmlkjihgfedcbaZYXWVUTSR The present study was undertaken to deter- mine the effect of two different types of liver cell proliferative stimuli, namely compensatory regeneration and direct hyperplasia on DNA synthesis of normal and preneoplastic isolated hepatocytes. Platelet-poor plasma (PPP) iso- lated from male Wistar rats treated with three different hepatomitogens, lead nitrate (l_N), cyproterone acetate (CPA) and ethylene di- bromide (EDB), or subjected to surgical partial hepatectomy (PH), was tested for its ability to stimulate DNA synthesis in normal and pre- neoplastic hepatocytes in primary cultures. In- duction of DNA synthesis was detected as ear- ly as 30 min after CPA, EDB and PH admini- stration and persisted up to 5 days after the LN administration. In addition, hepatocytes isola- ted from preneoplastic liuer nodules were also able to respond in culture to the DNA synthesis stimulus induced by these factors. Keywords: compensatory regeneration; direct hyperplasia; platelet-poor plasma; hepatocytes Correspondence to- P. Coni. lstituto di Patologia Sperimentale. Via Porcell 4. 09124 Cagliari, Italy. Characterization of factors that control liver cell proliferation remains a central issue in un- derstanding both normal and abnormal growth in this organ. Under normal circumstances, cell proliferation may be induced in resting tissue such as the liver by at least two different mech- anisms: (a), through compensatory regenera- tion after cell loss following PH or chemically induced necrosis and; (b), through direct hy- perplasia following administration of various mitogens. Our early studies indicate that, unlike com- pensatory liver cell proliferation, direct hyper- plasia induced by liver mitogens such as lead nitrate (LN), ethylene dibromide (EDB) and cyproterone acetate (CPA) does not support carcinogen-induced initiation [ 1,2]. While the compensatory type of cell proliferation is a consequence of cell loss, the mitogenic stimulus has to overcome the growth control mechanisms normally operating in the liver. The target for the mitogen could be either the liver (receptors, endogenous factors, DNA, etc.) and/or other organs (exocrine glands, production of exogenous factors, etc.) [3]. The interaction between exogenous and endoge- nous variations could be the stimulus for the in- duction of cell proliferation in the liver, and 0304.3835/92/$05.00 0 1992 Elsevier Scientific Publishers Ireland Ltd Printed and Published in Ireland