ENHANCED SKIN CARCINOGENESIS IN TRANSGENIC MICE WITH HIGH EXPRESSION OF GLUTATHIONE-PEROXIDASE OR BOTH GLUTATHIONE-PEROXIDASE AND SUPEROXIDE-DISMUTASE

Female transgenic mice (C57BL/6 x CBA/J)F-1 with a I-fold increase in expression of glutathione peroxidase (GP) or with a 1-fold increase in the expression of GP and a 3-4-fold increase in the expression of sup eroxide dismutase (SOD) had an enhanced carcinogenic response to initi ation by 7,12-dimethylbenz[a]anthracene (DMBA) followed by promotion w ith 12-O-tetradecanoylphorbol-13-acetate (TPA). GP- or GP+SOD-transgen ic mice that were initiated by a single topical application of 200 nmo l of DMBA followed by promotion with 8 nmol of TPA twice weekly fur 30 weeks developed an average of 10,9 ol 11.0 skin tumors per mouse and a 100% tumor incidence in comparison with the corresponding nontransge nic mice, which had 3.9 tumors per mouse and an 83% tumor incidence, A fter stopping TPA application, partial sl;in tumor regression occurred more rapidly in nontransgenic mice than in either type of transgenic mouse, At 10 weeks after termination of TPA treatment, 9-11% of the tu mor-bearing transgenic mite and 26% of the tumor-bearing nontransgenic mice had complete regression of their tumors, Histopathological exami nation of 96 skin papillomas revealed that the area, location, degree of tumor dysplasia, bromodeoxyuridine labeling index, and p53 protein levels were closely intercorrelated, Further analysis indicated that p apillomas with the same grade of dysplasia had a higher bromodeoxyurid ine labeling index and a greater p53 protein level in GP- or GP+SOD-tr ansgenic mice than those in nontransgenic mice, The data indicated tha t overexpression of skin antioxidant enzymes GP or GP+SOD, which are e nzymes that are believed to protect cells from oxidative damage by sca venging reactive oxygen species, lead to the increased, rather than th e decreased, tumorigenesis in a DMBA/TPA two-stage skin carcinogenesis model.