HIGH STEREOSELECTIVITY AMONG THE OPTICAL ISOMERS OF THE DIASTEREOMERIC BAY-REGION DIOL-EPOXIDES OF BENZ(A)ANTHRACENE IN THE EXPRESSION OF TUMORIGENIC ACTIVITY IN MURINE TUMOR-MODELS

  • 1 January 1984
    • journal article
    • research article
    • Vol. 44  (3) , 929-933
Abstract
The tumorigenicity of the (+)- and (-)-enantiomers of the diastereomeric bay-region benz(a)anthracene 3,4-diol-1,2-epoxides was evaluated in 2 mouse tumor models. In an initiation-promotion experiment on mouse skin, a single topical application of 0.1 or 0.4 .mu.mol of the benz(a)anthracene diol-epoxides was followed by 25 wk of promotion with 12-O-tetradecanoylphorbol-13-acetate. Of the 4 isomers of the bay-region diol-epoxides, only (+)-[1R,2S,3S,4R]-3,4-dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrobenz(a)anthracene[(+)-diol-epoxide-2] and (+)-[1R,2S,3S,4S]-3,4-dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrobenz(a)anthracene[(+)-diol-epoxide-1] had significant tumor-initiating activity. (+)-Diol-epoxide-2 was .apprx. 4-fold more active as a tumor initiator on mouse skin than was (+)-diol-epoxide-1 at both doses tested. In newborn mice, a total of 0.14 .mu.mol of compound, divided into 3 doses, was administered i.p. on the 1st, 8th and 15th days of life, and tumorigenic activity was determined when the mice were 26-32 wk of age. As was observed in the initiation-promotion experiment on mouse skin, only 2 of the 4 optical isomers of the bay-region diol-epoxides produced a significant tumor incidence. (+)-Diol-epoxide-2 induced a 100% incidence of lung tumors, with an average of 23.11 tumors/mouse, and was .gtoreq. 60-fold more active (average number of tumors per mouse) than was (+)-diol-epoxide-1, which produced a 31% lung tumor incidence and 0.38 lung tumors/mouse. (+)-Diol-epoxide-2 was the only optical isomer that induced a significant incidence of hepatic tumors in male mice (31% incidence, 1.17 tumors/mouse). The highly tumorigenic (+)-diol-epoxide-2 isomer with [R,S,S,R] absolute configuration has the same absolute configuration as does the highly tumorigenic isomer of the bay-region diol-epoxides of benzo(a)pyrene and chrysene.