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) mice were obtained applying a bi-directional selective breeding approach to a two-stage skin carcinogenesis protocol, using 9,10-dimethyl-1,2-benzanthracene (DMBA) as initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as promoter. Sixteen generations of selection produced a remarkable interline difference in responsiveness to two-stage skin carcinogenesis between Car-R and Car-S: identical DMBA (25 microgram) and TPA (5 microgram) doses induced papillomas in 100% of Car-S compared with 3.3% of Car-R mice and maximal responses of 14.3 or 0.03 papillomas/mouse, respectively, despite the shorter promotion applied to Car-S (49 vs. 208 days). To define the factors determining this great difference, Car-R and Car-S mice were challenged by initiators/promoters chemically unrelated to those used for selection. Both lines were subjected to either initiation by N-methyl-N-nitrosourea (MNU) followed by TPA promotion, or promotion by benzoyl peroxide, or 1,8-dihydroxy-3-methyl-9-anthrone (chrysarobin) following DMBA initiation. Initiation with MNU induced a 10-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 markedly in susceptibility to benzoyl peroxide promotion: Car-S mice initiated with 25 microgram DMBA and promoted with 7.5 mg benzoyl peroxide showed a 12-fold tumour incidence and a 103-fold tumour induction rate compared with the corresponding 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 MNU-initiated mice. Benzoyl peroxide was also able to promote carcinoma development in Car-S mice, though with a lower incidence (30.4%) than TPA.
Saran
A
A
Division of Protection of Man and the Ecosystems, ENEA CR-Casaccia, Rome, Italy. saran@casaccia.enea.it
Pazzaglia
S
S
Rebessi
S
S
Bouthillier
Y
Y
Pioli
C
C
Covelli
V
V
Mouton
D
D
Doria
G
G
Biozzi
G
G
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D000873:Anthracenes / Q000633:toxicity; D001585:Benzoyl Peroxide / Q000633:toxicity; D002277:Carcinoma / Q000139:chemically induced / Q000235:genetics; D008770:Methylnitrosourea / Q000633:toxicity; D051379:Mice; D008815:Mice, Inbred Strains; D010212:Papilloma / Q000139:chemically induced / Q000235:genetics; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000235:genetics; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity
D000873:Anthracenes; D015127:9,10-Dimethyl-1,2-benzanthracene; C013883:chrysarobin; D008770:Methylnitrosourea; D013755:Tetradecanoylphorbol Acetate; D001585:Benzoyl Peroxide