The influence of initiator dose and promoter dose, duration, and type on the progression of
papillomas to
carcinomas was examined in Sencar mice. A good dose-response relationship for promotion of
papilloma formation by 12-O-tetradecanoylphorbol-13-acetate (TPA) [following initiation with 6.5 micrograms of
7,12-dimethylbenz(a)anthracene (DMBA)] was observed in the range of 0.125 to 2.0 micrograms/mouse. A maximal
papilloma response was induced with 2 micrograms/mouse (24
papillomas/mouse). When adjusted for mortality, the
carcinoma incidence after 60 wk of promotion was essentially the same (approximately 80%) for doses above 0.5 micrograms/mouse. In a related experiment, mice were given an initiation dose of either 2 or 20 micrograms of DMBA followed by applications of 2 micrograms of TPA for 3, 5, 7, or 60 wk.
Papilloma formation was proportional to length of treatment, with a maximum of 29
papillomas/mouse (20-micrograms initiating dose of DMBA) and 10
papillomas/mouse (2-micrograms initiating dose of DMBA) occurring between 10 and 15 wk of promotion. In this experiment, the
carcinoma incidence was clearly proportional to the duration of promoter treatment at the low initiation dose of DMBA. The
carcinoma incidence, on the other hand, was similar (approximately 70%) in groups of mice given an initiation dose of 20 micrograms of DMBA and promotion treatment for greater than or equal to 5 wk. Thus, the initiator dose had a dramatic effect on the outcome of these experiments. Additional experiments were performed to compare
tumor progression with the
anthrone promoter,
chrysarobin. At optimal promoting doses,
chrysarobin treatment produced a maximum number of
papillomas that was approximately 1/3 that produced by TPA (6.4 versus 17.0
papillomas per mouse, respectively). However, the
carcinoma response was very similar in these two treatment groups, confirming previous work from this laboratory. In addition,
chrysarobin treatment following 10 wk of TPA promotion did not enhance the progression of preexisting
papillomas to
carcinomas. The data presented in this paper are consistent with a model in which several types or stages of
papillomas are initially produced during two-stage
carcinogenesis in mouse skin with different probabilities of progressing to
carcinomas. However, the data indicate that optimal doses of promoter and initiator exist and can influence interpretation of
tumor progression studies in mouse skin.