Skin tumorigenesis by initiators and promoters of different chemical structures in lines of mice selectively bred for resistance (Car-R) or susceptibility (Car-S) to two-stage skin carcinogenesis

Carcinogenesis-resistant (Car-R) and carcinogenesis-susceptible (Car-S) mic e were obtained applying a bi-directional selective breeding approach to a two-stage skin carcinogenesis protocol, using 9,10-dimethyl-1,2-benzanthrac ene (DMBA) as initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as p romoter. Sixteen generations of selection produced a remarkable interline d ifference in responsiveness to two-stage skin carcinogenesis between Car-R and Car-S: identical DMBA (25 mu g) and TPA (5 mu g) doses induced papillom as in 100% of Car-S compared with 3.3% of Car-R mice and maximal responses of 14.3 or 0.03 papillormas/mouse, respectively, despite the shorter promot ion applied to Car-S (49 vs. 208 days). To define the factors determining t his great difference, Car-R and Car-S mice were challenged by initiators/pr omoters chemically unrelated to those used for selection. Both lines were s ubjected to either initiation by N-methyl-N-nitrosourea (MNU) followed by T PA promotion, or promotion by benzoyl peroxide, or 1,8-dihydroxy-3-methyl-9 -anthrone (chrysarobin) following DMBA initiation. Initiation with MNU indu ced a IO-fold tumour incidence in Car-S compared with Car-R mice, and a 32- fold difference in tumour induction rate. The 2 lines also differed markedl y in susceptibility to benzoyl peroxide promotion: Car-S mice initiated wit h 25 mu g DMBA and promoted with 7.5 mg benzoyl peroxide showed a 12-fold t umour incidence and a 103-fold tumour induction rate compared with the corr esponding Car-R group. Both lines, however, were refractory to chrysarobin promotion. The progression of papillomas to carcinomas was examined in all Car-S groups. The incidence of mice that developed carcinomas was 57% in MN U-initiated mice. Benzoyl peroxide was also able to promote carcinoma devel opment in Car-S mice, though with a lower incidence (C) 1999 Wiley-Liss, In c.