Critical biochemical and regulatory events in malignant transformation in vitro

Oncogenic transformation of hamster embryo cells and mouse C3H 10T1/2 can be modified by a variety of agents and conditions which alter events at early stages of initiation and at later stages of promotion. Inhibition of poly(ADP-ribose) synthesis by low concentrations of benzamide and 3-aminobenzamide inhibits the induction of transformation by ultraviolet light, X-rays, and chemical carcinogens as well as inhibiting the enhancement of transformation by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). The suppression of transformation by the benzamides is observed under conditions where the inhibitors reduce poly(ADP-polymerization) by about 75%, have no influence on damage induced by X-rays or alkylating chemicals and enhance sister chromatid exchanges. A modification of the physiological state of the cells by rendering them hypothyroid also results in an inhibition of transformation by radiation and chemical carcinogens and a suppression of promotion by teleocidin and TPA. When thyroid hormone is added to the medium radiogenic transformation and its dramatic enhancement by the tumor promoters is observed, with teleocidin being over 100 times as effective as a promotor as TPA. Our results suggest that mechanisms regulating initiation and promotion are associated with alterations in poly(ADP-ribosylation), causing changes in gene control and expression and may differ from those associated with the induction of sister chromatid exchanges. The results also suggest that genetic events taking place in both the early events (initiation) and late events (promotion) in malignant transformation are highly dependent on the presence of thyroid hormones.