Comparison of the tumor-initiating activity of 7,12-dimethylbenz[a]anthracene and benzo[a]pyrene in female SENCAR and CD-1 mice

The derivation of mice resistant and susceptible to skin tumorigenesisusing the initiation-promotion regimen is described. Dose-responserelationships for tumor-initiating activities of 7,12-dimethylbenz[a]-anthracene(DMBA) and benzo[a]pyrene (BP) in the susceptible line (SENCAR)are presented. A single topical dose of either 0.1, 1.0, 10or 100 nmol DMBA, followed one week later by twice weekly applicationsof 8.5 nmol 12–0-tetradecanoylphorbol-13-acetate (TPA)for 19 weeks, produced 0, 3.3, 4.9 and 23.1 papillomas per mouse,respectively. Single topical initiating doses of either 50,100 or 200 nmol BP produced 1.7, 3.8 or 7.8 papillomas per mouse,respectively, after 28 weeks of promotion with 8.5 nmol TPA.SENCAR mice were compared with CD-1 mice for the initiatingactivity of DMBA and BP. Initiating doses of 0.1, 1.0, 10 and100 nmol DMBA produced 0.6, 3.8, 7.0 and 24 papillomas per mouse,respectively, in SENCAR mice and in CD-1 mice produced 0, 0.2,3.0 and 5.6 papillomas per mouse, respectively, after 25 weeksof promotion with TPA. With BP as the initiator, 10, 50, 100and 200 nmol doses produced 0.9, 1.6, 3.8 and 8.3 papillomasper mouse, respectively, in SENCAR mice and in CD-1 mice produced0.1, 0.7,1.8 and 3.8 papillomas per mouse, respectively, after25 weeks of promotion with TPA. SENCAR mice were compared with CD-1 mice for possible differencesin the oxidative metabolism of DMBA using epidermal homogenatesas the enzyme source. Basal levels of monooxygenase activitytoward DMBA were similar in both mouse stocks. Epidermal monooxygenaseactivities following pre-treatment with inducers including DMBA,3-methylcholanthrene, dibenz[a,c]anthracene, Aroclor 1254 and2,3,7,8-tetrachlorodibenzo-p-dioxin, also were quite similarin both mouse stocks. High-pressure liquid chromatographic profilesof ethyl acetate/ acetone (2:1) extractable metabolites revealeda close similarity in the patterns as well as the rates of formationof specific metabolites. Metabolites of DMBA tentatively identifiedbased on cochromato-graphy with purified reference standardsincluded phenols, 12-hydroxymethyl-7-methylbenz[a]anthracene,7-hydroxymethyl-12-methylbenz[a]antnracene, 7,12-dihydroxymethylbenz[a]anthracene,(±)-trans-8,9-dihydro-8,9-dihydroxy-7,12-dimethylbenz[a]anthraceneand (±)-trans-5,6-dihydro-5,6-dihydroxy-7,12-dimethylbenz[a]anthracene.The results suggested that differences in oxidative metabolismof DMBA were not responsible for the differences in sensitivityto tumor-initiation between SENCAR and CD-1 mice.