Two-stage carcinogenesis in the planarian

Abstract

Healthy freshwater planarians of the species Dugesia dorotocephala (Woodworth) were exposed to 0.3 mg 1-1 cadmium and to 0.01 mg 1-1 TPA (12-O-tetradecanoyl-phorbol-13-acetate) in various combinations of order and duration. Exposure to cadmium followed by exposure to TPA induced tumors in 50% of the animals only after 12 d exposure to each carcinogen. Reversed order of exposure, i.e., to TPA followed by cadmium, produced tumors in about 18% of the planarians, a rate similar to that in animals exposed to TPA alone. Cadmium by itself, however, did not produce tumors. These findings indicate that cadmium is mutagenic and acts as an initiator, whereas TPA is epigenetic and acts as a promoter. Ultimate damage to DNA or to the DNA-repair system appears to occur during the first 12 d of cadmium treatment. A second set of experiments was done exposing planarians first to cadmium and then to TPA for 2 weeks either immediately or after a 2-,4-,8-, or 16-week hiatus. Tumors were induced in approximately 52–54% of planarians treated with TPA within 4 weeks of their exposure to cadmium but in only 18–20% of planarians treated with TPA 8 and 16 weeks after exposure to cadmium (i.e., at a rate similar to that with TPA alone). These results indicate that exposure to cadmium alone induces mutagenic changes that persist for a period of time (less than 8 weeks) but that subsequent exposure to TPA within that period is necessary to induce tumors. Planarians are excellent models for study of the mechanisms of the initiation and promotion of tumors.