The characteristics of the skin
tumor promotion response with
anthrone derivatives has been further examined in SENCAR mice.
Chrysarobin (1,8-dihydroxy-3-methyl-9-anthrone) was an effective skin
tumor promoter when applied twice weekly with dose-dependent increases in both
papillomas and
squamous cell carcinomas between 25 and 100 nmol/mouse. A similar dose-response relationship for
papilloma and
carcinoma formation was observed when
chrysarobin was applied once weekly. Interestingly,
chrysarobin was approximately twice as active as a skin
tumor promoter when applied once weekly versus twice weekly. Doses of 25,100, and 220 nmol/mouse gave maximal
papilloma responses of 2.90, 8.15, and 9.38 versus 0.73, 4.70, and 5.42
papillomas/mouse, respectively, in mice initiated with 25 nmol
7,12-dimethylbenz(a)anthracene. Thus, unlike 12-O-tetradecanoylphorbol-13-acetate (TPA), where a twice weekly application frequency is optimal, application of
anthrone promoters such as
chrysarobin once weekly is a more optimal frequency for
papilloma development.
Chrysarobin was also a much more effective skin
tumor promoter when the start of promotion was delayed by an additional 10 weeks. Thus, groups of mice initiated with 10 nmol
7,12-dimethylbenz(a)anthracene and having promotion started in either the 3rd or the 13th week after initiation had maximal responses of 5.6 or 11.0
papillomas/mouse, respectively. In addition, the rate of
papilloma development was faster in the delayed promotion group. The progression of
papillomas to
carcinomas was examined in all
chrysarobin-treated groups and compared with three groups of mice treated with 3.4 nmol TPA. After 60 weeks of promotion, the
anthrone promoter-treated groups had
carcinoma:
papilloma ratios 2.5 to 5.0 times higher than the TPA-treated groups. This was due primarily to the fact that similar
carcinoma responses were observed in both
anthrone- and TPA-treated mice at optimal promoting doses whereas the
papilloma responses were significantly lower in the former groups. The data suggest that
anthrone derivatives are very efficient
tumor promoters. The results are further discussed in terms of mechanisms of skin
tumor promotion.