The tumorigenicities of 7-methylbenz[c]
acridine (7MB[c]ACR) and its five metabolically possible trans-dihydrodiols were determined in two mouse
tumor models. In initiation-promotion studies on mouse skin, a single topical application of 0.15 to 0.75 mumol of compound was followed 9 days later by twice weekly applications of 12-O-tetradecanoylphorbol-13-acetate for 20 wk. Comparison of the average number of skin
tumors per mouse indicated that 7MB[c]ACR 3,4-dihydrodiol, the metabolic precursor of a bay-region diol-
epoxide, was 4- to 6-fold more active than the parent compound as a
tumor initiator. The 1,2-, 5,6-, 8,9-, and 10,11-dihydrodiols of 7MB[c]ACR had no significant
tumor-initiating activity at the doses tested. In newborn mice, a total dose of 0.35 mumol of compound was administered i.p. during the first 15 days of life, and tumorigenic activity was determined when the mice were 32 to 36 wk old. 7MB[c]ACR 3,4-dihydrodiol induced about 8-fold more pulmonary
tumors per mouse and 9-fold more hepatic
tumors per male mouse than the parent aza-substituted
hydrocarbon. The other four dihydrodiols of 7MB[c]ACR had no significant tumorigenic activity. The high tumorigenic activity of 7MB[c]ACR 3,4-dihydrodiol in both
tumor models suggests that a bay-region 3,4-diol-1,2-epoxide may be an ultimate carcinogenic metabolite of 7MB[c]ACR. 7MB[c]ACR was at least 5-fold more active as a
tumor initiator on mouse skin than was the unsubstituted aza-aromatic compound,
benz[c]acridine. This latter result indicates that substitution of a methyl group at position 7 of
benz[c]acridine leads to enhanced
tumor-initiating activity, as has been previously demonstrated for
benz[a]anthracene and its 7-methyl derivative.