Influence of dose of initiator on two-stage skin carcinogenesis in BALB/c mice with cellular mosaicism

We examined the effects of initiation with different doses of 7,12-dimethylbenz[a]anthracene (DMBA) on two-stage skin carcinogenesis in BALB/c mice. The induction of skin papillomas and their sequential tumor progression were followed by determination of locations of the tumors on the back of each mouse, by histological evaluation and by determining the phosphoglycerate kinase (PGK) phenotypes of neoplasms. Three doses of DMBA were tested, 20.0, 2.0 and 0.2 micrograms. Lowering the dose of DMBA initiation prolonged tumor latency and reduced tumor susceptibility and frequency. All of the papillomas that developed with the lowest dose of DMBA initiation were found to be clonal by PGK analysis and each of them was promoter dependent; termination of TPA promotion led to its regression. The 0.2-micrograms DMBA initiation dose also reduced to zero the delayed promoter-independent papillomas and the frequency of papillomas changing their PGK phenotype during tumor progression. Thus, these studies provide evidence that the carcinogen not only causes initiation in mouse skin epidermal cells but also that the dose of carcinogen strongly influences the mode of growth of the initiated cells to papillomas and the progression of these tumors.