15-16-dihydro-11-methylcyclopenta(a)phenanthren-17-one and Breast-Neoplasms

The increase in carcinogenicity of polycyclic aromatic compounds following bay-region methyl group substitution involves a steric component: increasing the size of the alkyl substituent decreases the carcinogenic activity of the compound. To determine whether there is also an electronic component to this effect, we synthesized a bay-region 11-trifluoromethyl analogue of 15,16-dihydrocyclopenta[alpha]phenanthren-17-one which is sterically similar but electronically very different from the 11-methyl derivative. This trifluoromethyl derivative bound to DNA in cultures of the human mammary carcinoma cell line MCF-7 to a much lower extent than the methyl-substituted compound. The trifluoromethyl derivative did not form detectable levels of DNA adducts in the epidermis of Sencar mice and was inactive as an initiator after promotion with 12-O-tetradecanoylphorbol-13-acetate for 20 weeks. In contrast, the 11-methyl derivative formed > 3 pmol adducts/mg DNA and initiated eight papillomas per mouse. These data indicate that both the steric configuration and the electronic nature of a bay-region substituent are important in determining the overall effect of the substituent on the biological activity of the molecule.

Topics: Animals; Breast Neoplasms; Carcinogens; Cell Line; DNA; DNA Adducts; Epidermis; Female; Gonanes; Humans; Methylation; Mice; Mice, Inbred SENCAR; Skin Neoplasms; Structure-Activity Relationship; Tetradecanoylphorbol Acetate; Time Factors; Tumor Cells, Cultured