Benz[c]acridine (B[c]ACR) and 12 of its derivatives, including the 5 metabolically possible trans-dihydrodiols, the diastereomeric bay-region diol-
epoxides, 2 non-bay-region diol-
epoxides, and the K-region arene
oxide, were tested for
tumor-initiating activity on mouse skin. A single topical application of 0.4 to 2.5 mumol of compound was followed 12 days later by twice-weekly applications of the
tumor promoter 12-O-tetradecanoylphorbol-13-acetate for 25 weeks. B[c]ACR was a weak
tumor initiator on mouse skin, producing a 37%
tumor incidence and 1.33
tumors/mouse at the 2.5-mumol dose. Of the five metabolically possible trans-dihydrodiols of B[c]ACR, only trans-3,4-dihydroxy-3,4-dihydro-B[c]ACR had significant
tumor-initiating activity. This compound was at least 6-fold more active than was the parent compound at the three doses tested. The diastereomeric bay-region diol-
epoxides, in which the
epoxide oxygen is either cis(isomer 1) or trans (isomer 2) to the benzylic
hydroxyl group, each had significant
tumor-initiating activity, although isomer 2 was at least 5-fold more active than was isomer 1 and had activity equal to that of its potential metabolic precursor, trans-3,4-dihydroxy-3,4-dihydro-B[c]ACR. Two non-bay-region diol-
epoxides (isomer 2 of the 8,9-diol-10,11-
epoxide and the 10,11-diol-8,9-
epoxide) and the 5,6-arene
oxide (K-region) were inactive at the doses tested. 3,4-Dihydro-B[c]ACR, the potential metabolic precursor of a bay-region tetrahydroepoxide, was the most potent
tumor initiator analyzed in the present study. At an initiating dose of 0.4 mumol, this compound produced a 97%
tumor incidence and 7.90
tumors/mouse after 15 weeks of promotion with 12-O-tetradecanoylphorbol-13-acetate. These results suggest that B[c]ACR, the N-12 analogue of
benz[a]anthracene, undergoes metabolic activation to an ultimate carcinogenic metabolite via formation of a bay-region diol-
epoxide, as has already been demonstrated for
benz[a]anthracene.