Transgenic mouse models in carcinogenesis research and testing

Double transgenic mice bearing fusion genes consisting of mouse albumin enh ancer/promoter-mouse c-myc cDNA and mouse metallothionein 1 promoter-human TGF-alpha cDNA were generated to investigate the interaction of these genes in hepatic oncogenesis and to provide a general paradigm for characterizin g both the interaction of nuclear oncogenes and growth factors in tumorigen esis. In addition, these mice provide an experimental model to test how env ironmental chemicals might interact with the c-myc and TGF-alpha transgenes during the neoplastic process. We show experimental evidence that co-expre ssion of TGF-alpha and c-myc transgenes in mouse liver promotes overproduct ion of ROS and thus creates an oxidative stress environment. This phenomeno n may account for the massive DNA damage and acceleration of hepatocarcinog enesis observed in the TGF-alpha/c-myc mouse model. Also, the role of mutag enesis in hepatocarcinogenesis induced by 2-amino-3,8-dimethylimidazo(4,5-f )-quinoxaline (MeIQx) was demonstrated in C57BL/lacZ (Muta(TM) Mice) and do uble transgenic c-myc/lacZ mice that carry the lacZ mutation reporter gene. The MeLQx hepatocarcinogenicity was associated with an increase in in vivo mutagenicity as scored by mutations in the lacZ reporter gene. These resul ts suggest that transgenic mouse models may provide important tools for tes ting both the carcinogenic potential of environmental chemicals and the int eraction/cooperation of these compounds with specific genes during the neop lastic process. Published by Elsevier Science Ireland Ltd.