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Both (±)syn- and (±)anti-7,12-Dimethylbenz[a]anthracene-3,4-diol-1,2-epoxides Initiate Tumors in Mouse Skin That Possess -CAA- to -CTA- Mutations at Codon 61 of c-H-ras¹

Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987 [M-s. T., J. X. C., D. S. B.]; Department of Carcinogenesis, University of Texas M. D. Anderson Cancer Center, Science, [S. V. V., J. D.]; Department of Cancer Causation and Prevention, AMC-Cancer Research Center, Denver, Colorado 80214 [A. V., T. J. S.]; Lankenau Medical Research Center, Wynnewood, Pennsylvania 19096 [R. J. M.]; and Ben May Institute, University of Chicago, Chicago, Illinois 60637 [R. G. H.]

We have determined the tumor-initiating activity of (±)syn- and (±)anti-7,12-dimethylbenz[a]anthracene-3,4-diol-1,2-epoxide (syn- and anti-DMBADE), the two metabolically formed bay-region diol epoxides of DMBA, and we have also analyzed mutations in the H-ras gene from tumors induced by these compounds. Using a two-stage, initiation-promotion protocol for tumorigenesis in mouse skin, we have found that both syn- and anti-DMBADE are active tumor initiators, and that the occurrence of papillomas is carcinogen dose dependent. All of the papillomas induced by syn-DMBADE (a total of 40 mice), 96% of those induced by anti-DMBADE (a total of 25 mice), and 94% of those induced by DMBA (a total of 16 mice) possessed a -CAA- to -CTA- mutation at codon 61 of H-ras. No mutations in codons 12 or 13 were detected in any tumor. Topical application of syn- and anti-DMBADE produced stable adducts in mouse epidermal DNA, most of which comigrated with stable DNA adducts formed after topical application of DMBA. Further analysis of the data showed that levels of the major syn- and anti-DMBADE-deoxyadenosine adducts formed after topical application of DMBA are sufficient to account for the tumor-initiating activity of this carcinogen on mouse skin. Previously, we showed that both the syn- and anti-DMBADE bind to the adenine (A¹⁸²) at codon 61 of H-ras. Collectively, these results indicate that the adenine adducts induced by both bay-region diol epoxides of DMBA lead to the mutation at codon 61 of H-ras and, consequently, initiate tumorigenesis in mouse skin.

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