Skin Tumors Initiated With DibenzCaJanthracene and Derivatives

This study was designed to evaluate the point mutations in the murine c-Ha-ras gene of skin papillomas induced by initiation wi th dibenz[a,jJanthracene (DB[a,jlA). its bay-region anti-diol epoxide (( +)anti-DB[a,jlA-DE), and a 7,14-dimethyl analogue (7,14-diMeDB[a,jlA). Recent studies (Nair RV, et al., Chem Res Toxicol 4: 11 5-122, 1991) in our laboratory have revealed both deoxyguanosine (dGuo) and deoxyadenosine (dAdo) adductsformed from the antiand syn-diol epoxides o f DB[a,]lA in cultured mouse epidermal cells after exposure t o this hydrocarbon. Using PCR amplification and direct sequencing, we found specific A182+T transversion mutations (eight of 10 tumors) in codon 61 of c-Ha-ras in papillomas induced by initiation wi th DB[a,jlA. Analysis of papillomas generated by initiation with the more biologically potent analogue 7,14-diMeDB[a,jlA revealed that five of five tumors exhibited A182+T transversions in codon 61. The nature o f the changes in the two DB[a,jIA tumors not showing codon 61 mutations in Ha-ras is currently not known since these tumor DNAs also did not possess c-Ha-rasmutations at codons 12,13, or 59. Interestingly, papillomas produced by initiation with (?)anti-DB[a,j]A-DE also possessed Af8*-tT transversion mutations in codon 61 o f c-Ha-ras (five o f five tumors). These data suggest that dAdo adducts derived from both parent hydrocarbons may play an important role in their tumor-initiating activity and possibly implicate a specific diol epoxide-dAdo adduct in this process.

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