2-STAGE EXPOSURE OF SYRIAN-HAMSTER-EMBRYO CELLS TO ENVIRONMENTAL CARCINOGENS - SUPERINDUCTION OF ORNITHINE DECARBOXYLASE CORRELATES WITH INCREASE OF MORPHOLOGICAL-TRANSFORMATION FREQUENCY

As part of environmental toxicology, it is important to assess both th e carcinogenic potential of xenobiotics and their mode of action on ta rget cells. Since dysregulation of ornithine decarboxylase (ODC), a ra te-limiting enzyme of polyamine biosynthesis, is considered as an earl y and essential component in the process of multistage carcinogenesis, we have studied the mode of ODC induction in Syrian-hamster-embryo(SH E) cells stage-exposed to carcinogens and to non-carcinogens. One-stag e (5 hr) treatment of SHE cells with 50 mu M clofibrate (CLF), a non-g enotoxic carcinogen, or with 0.4 mu M benzo(a)pyrene (BaP), a genotoxi c carcinogen, slightly decreased basal ODC activity. Using the 2-stage exposure, 1 hr to carcinogen, then replacement by TPA for 5 hr, the O DC activity was higher than that obtained with TPA alone. This ODC sup erinduction was not observed when SHE cells were similarly pre-treated with non-carcinogenic compounds. Several environmental chemicals, pes ticides, solvents, oxidizers and drugs were investigated with this SHE cell model. With one-stage exposure, some xenobiotics decreased basal ODC activity, while for others ODC changes were not noticeable. With 2-stage exposure (chemical followed by TPA), all carcinogens amplified the TPA-inducing effect, resulting in ODC superinduction. Comparative studies of the action of carcinogens and of non-carcinogens, using 2- stage exposure protocols, clearly show a close relationship between OD C induction rate and morphological transformation frequency. (C) 1998 Wiley-Liss, Inc.